Antithrombotic compounds

ABSTRACT

Antithrombotic compounds of general formula  
                 
 
     Exemplary are:  
     (1) 2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[ 3 -methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine,  
     (2) N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine, and  
     (3) N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/268,569,filed on Feb. 15, 2001is hereby claimed.

DESCRIPTION OF THE INVENTION

[0002] The present invention relates to the compounds of general formula

[0003] the tautomers, the stereoisomers, the mixtures, the prodrugs, thederivatives thereof which contain a group that is negatively chargedunder physiological conditions instead of a carboxy group, and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases which have valuable properties.

[0004] The compounds of the above general formula I wherein Ar denotes aphenyl or naphthyl group substituted by the groups R₅, R₆ and R₇, and R₅denotes a cyano group, are valuable intermediate products for preparingthe corresponding compounds of general formula I wherein R₅ denotes anamidino group optionally substituted by one or two C₁₋₃-alkyl groups.The compounds of the above general formula I with the exception of thosecompounds wherein Ar denotes a phenyl or naphthyl group substituted bythe groups R₅, R₆ and R₇, and R₅ denotes a cyano group, as well as thetautomers, the stereoisomers, the mixtures, the prodrugs, thederivatives thereof which contain a group that is negatively chargedunder physiological conditions instead of a carboxy group, and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids, and the stereoisomers thereof, have valuablepharmacological properties, particularly an antithrombotic activity andan inhibiting effect on factor Xa.

[0005] The present application thus relates to the new compounds of theabove general formula I and the preparation thereof, the pharmaceuticalcompositions containing the pharmacologically effective compounds, theirpreparation and use.

[0006] In the above general formula

[0007] (i) m denotes the number 0,

[0008] n denotes the number 1 and

[0009] A denotes a straight-chain C₁₋₃-alkylene group wherein

[0010] one or two hydrogen atoms independently of one another may bereplaced in each case by a C₁₋₃-alkyl group or

[0011] a hydrogen atom may be replaced by the group '(CH₂)_(p)—R_(f),while

[0012] p denotes one of the numbers 0, 1, 2 or 3 and

[0013] R_(f) denotes a hydroxycarbonyl, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,C₃₋₇-cycloalkylamino-carbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group, or

[0014] (ii) m denotes the number 1,

[0015] n denotes the number 1 and

[0016] A denotes a bond or

[0017] (iii) m denotes the number 0 or 1,

[0018] n denotes the number 0 and

[0019] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group, or

[0020] (iv) m denotes the number 2,

[0021] n denotes the number 0 and

[0022] A denotes a bond,

[0023] R₁ denotes an amino, C₁₋₅-alkylamino, C₃₋₇-cycloalkylamino orphenyl-C₁₋₃-alkylamino group each of which may be substituted at theamino nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by aC₁₋₃-alkyl or C₁₋₃-alkyl-carbonyl group optionally substituted in thealkyl moiety by a carboxy group, a group which may be converted in vivointo a carboxy group, an amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup,

[0024] a di-(C₁₋₅-alkyl)amino or N-(C₃₋₇-cycloalkyl)-C₁₋₅-alkylaminogroup, while the C₁₋₅-alkyl moiety with the exception of the 1 positionmay be substituted in each case by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkyl-amino or di-(C₁₋₃-alkyl)-amino group,

[0025] a 4- to 7-membered cycloalkyleneiminocarbonyl orcycloalkyleneiminosulphonyl group optionally substituted by aC₁₋₃-alkyl, amino-C₁₋₃-alkyl, C₁₋₃-alkylamino-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, aminocarbonyl,C₁₋₃-alkylamino-carbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group,

[0026] a 2,5-dihydropyrrol-1-yl-carbonyl group,

[0027] an aminosulphonyl group optionally substituted by one or twoC₁₋₃-alkyl groups,

[0028] a C₃₋₇-cycloalkyl-carbonyl group, whilst

[0029] the methylene group in the 3 or 4 position in aC₅₋₇-cycloalkyl-carbonyl group may be replaced by an —NH group wherein

[0030] the hydrogen atom of the —NH group may be replaced by aC₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, phenylcarbonyl or phenylsulphonylgroup,

[0031] a phenylcarbonyl or heteroarylcarbonyl group,

[0032] or a C₁₋₃-alkyl group optionally monosubstituted by an amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, phenyl or a 4- to7-membered cycloalkyleneimino group or terminally disubstituted by aphenyl group and a hydroxy group, while

[0033] the phenyl substituents may be substituted by an amidino groupoptionally substituted by one or two C₁₋₃-alkyl groups, by a fluorine,chlorine or bromine atom, by a trifluoromethyl, C₁₋₃-alkyl orC₁₋₃-alkoxy group,

[0034] R₂ denotes a hydrogen, fluorine, chlorine or bromine atom, aC₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partlyreplaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, hydroxy,C₁₋₃-alkoxy or trifluoromethoxy group,

[0035] R₃ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0036] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group optionallysubstituted by a carboxy group or a group which may be converted in vivointo a carboxy group and

[0037] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while

[0038] R₅ denotes a cyano group, an amidino group optionally substitutedby one or two C₁₋₃-alkyl groups, an amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl or di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyl group,

[0039] R₆ denotes a hydrogen, fluorine, chlorine or bromine atom, atrifluoromethyl, C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy,C₁₋₃-alkoxy-C₁₋₃-alkyl, carboxy, carboxy-C₁₋₃-alkyl,carboxy-C₁₋₃-alkoxy, C₁₋₄-alkoxy-carbonyloxy,C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, phenyl-C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)amino group and

[0040] R₇ denotes a hydrogen, fluorine, chlorine or bromine atom or aC₁₋₃-alkyl group,

[0041] or a thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl group optionally substituted in the carbon skeleton by aC₁₋₃-alkyl group,

[0042] while the term heteroaryl group mentioned above denotes a5-membered heteroaryl group bound via a carbon or nitrogen atom whichcontains

[0043] an imino group optionally substituted by a C₁₋₄-alkyl orC₁₋₄-alkyl-carbonyl group, an oxygen or sulphur atom,

[0044] an imino group optionally substituted by a C₁₋₄-alkyl group or anoxygen or sulphur atom and additionally a nitrogen atom,

[0045] an imino group optionally substituted by a C₁₋₄-alkyl group andtwo nitrogen atoms or

[0046] an oxygen or sulphur atom and two nitrogen atoms,

[0047] or a 6-membered heteroaryl group which contains one or twonitrogen atoms,

[0048] while a phenyl ring may be fused to the abovementioned 5- or6-membered heteroaryl groups via two adjacent carbon atoms and thebicyclic heteroaryl groups thus formed may be bound via theheteroaromatic or carbocyclic moiety, and the unsubstituted ormonosubstituted phenyl groups mentioned in the definition of theabovementioned groups, or the unsubstituted or monosubstituted phenylmoieties contained in these groups, as well as the abovementionedheteroaryl groups may additionally be substituted at a carbon atom ineach case by a fluorine, chlorine or bromine atom, by a trifluoromethyl,C₁₋₃-alkyl or C₁₋₃-alkoxy group, unless otherwise stated.

[0049] The carboxy groups mentioned in the definition of theabovementioned groups may be replaced by a group which may be convertedin vivo into a carboxy group or by a group which is negatively chargedunder physiological conditions,

[0050] and moreover the amino and imino groups mentioned in thedefinition of the abovementioned groups may be substituted by a groupwhich can be cleaved in vivo. Such groups are described for example inWO 98/46576 and by N. M. Nielsen et al. in Inter-national Journal ofPharmaceutics 39, 75-85 (1987).

[0051] By a group which can be converted in vivo into a carboxy group ismeant, for example, a hydroxymethyl group, a carboxy group esterifiedwith an alcohol wherein the alcohol moiety is preferably a C₁₋₆-alkanol,a phenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, while a C₅₋₈-cycloalkanolmay additionally be substituted by one or two C₁₋₃-alkyl groups, aC₅₋₈-cycloalkanol wherein a methylene group in the 3 or 4 position isreplaced by an oxygen atom or by an imino group optionally substitutedby a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxycarbonyl orC₂₋₆-alkanoyl group and the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol orphenyl-C₃₋₅-alkynol with the proviso that no bonds to the oxygen atomstart from a carbon atom which carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol with a total of 8 to 10carbon atoms which may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R_(a)—CO—O—(R_(b)CR_(c))—OH,

[0052] wherein

[0053] R_(a) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl orphenyl-C₁₋₃-alkyl group,

[0054] R_(b) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl orphenyl group and

[0055] R_(c) denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0056] by a group which is negatively charged under physiologicalconditions is meant, for example, a tetrazol-5-yl,phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl,C₁₋₆-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl orperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group

[0057] and by a group which can be cleaved in vivo from an imino oramino group is meant, for example, a hydroxy group, an acyl group suchas a phenylcarbonyl group optionally mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups,while the substituents may be identical or different, a pyridinoyl groupor a C₁₋₁₆-alkanoyl group such as the formyl, acetyl, propionyl,butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl orallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxygroup, wherein hydrogen atoms may be wholly or partially replaced byfluorine or chlorine atoms such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl,methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy,propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy,tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy,octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy,undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, aphenyl-C₁₋₁₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionylgroup wherein the amino group may be mono- or disubstituted byC₁₋₆-alkyl or C₃₋₇-cycloalkyl groups and the substituents may beidentical or different, a C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(a)—CO—O—(R_(b)CR_(c))—O—CO—, C₁₋₆-alkyl-CO—NH—(R_(d)CR_(c))—O—CO— orC₁₋₆-alkyl-CO—O—(R_(d)CR_(e))—(R_(d)CR_(e))—O—CO— group, wherein R_(a)to R_(c) are as hereinbefore defined,

[0058] R_(d) and R_(e) which may be identical or different, denotehydrogen atoms or C₁₋₃-alkyl groups.

[0059] Moreover, the saturated alkyl and alkoxy moieties containing morethan 2 carbon atoms mentioned in the definitions above also include thebranched isomers thereof such as the isopropyl, tert.butyl, isobutylgroup, etc.

[0060] Preferred compounds of the above general formula I are thosewherein

[0061] (i) m denotes the number 0,

[0062] n denotes the number 1 and

[0063] A denotes a straight-chain C₁₋₃-alkylene group wherein

[0064] one or two hydrogen atoms independently of one another may bereplaced in each case by a C₁₋₃-alkyl group or

[0065] a hydrogen atom may be replaced by the group —(CH₂)_(p)—R_(f),while

[0066] p denotes one of the numbers 0, 1, 2 or 3 and

[0067] R_(f) denotes a hydroxycarbonyl, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,C₃₋₇-cycloalkylamino-carbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group, or

[0068] (ii) m denotes the number 0 or 1,

[0069] n denotes the number 0 and

[0070] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group,

[0071] R₁ denotes an amino, C₁₋₃-alkylamino or C₃₋₇-cycloalkylaminogroup each of which may be substituted at the amino nitrogen atom by aC₁₋₃-alkyl, C₁₋₃-alkylcarbonyl, carboxy-C₁₋₃-alkyl,carboxy-C₁₋₃-alkylcarbonyl, C₁₋₆-alkoxy-carbonyl-C₁₋₃-alkyl-carbonyl oramino-C₁₋₃-alkyl-carbonyl group,

[0072] a di-(C₁₋₃-alkyl)amino or N-(C₅₋₇-cycloalkyl)-C₁₋₃-alkylaminogroup,

[0073] a 4- to 7-membered cycloalkyleneiminocarbonyl group optionallysubstituted by a C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, aminocarbonyl or C₁₋₃-alkylamino-carbonylgroup, while

[0074] a hydrogen atom bound to a nitrogen atom may be replaced by anacetyl, phenylcarbonyl or tert.-butoxycarbonyl group,

[0075] or a 2,5-dihydropyrrol-1-yl-carbonyl group,

[0076] R₂ denotes a hydrogen, fluorine, chlorine or bromine atom, aC₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl, trifluoromethyl, C₁₋₃-alkoxy ortrifluoromethoxy group,

[0077] R₃ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0078] R₄ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0079] Ar denotes a phenyl group substituted by the groups R₅, R₆ andR₇, while

[0080] R₅ denotes a cyano group, an amidino group optionally substitutedby one or two C₁₋₃-alkyl groups, a hydroxy, C₁₋₆-alkoxy-carbonyl,2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or anamino-C₁₋₃-alkyl or C₁₋₃-alkylamino-C₁₋₃-alkyl group,

[0081] R₆ denotes a hydrogen, fluorine, chlorine or bromine atom, atrifluoromethyl, C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy,carboxy, C₁₋₃-alkoxy-carbonyloxy, carboxy-C₁₋₃-alkoxy orC₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy group and

[0082] R₇ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0083] while the unsubstituted or monosubstituted phenyl groupsmentioned in the definition of the abovementioned groups, or theunsubstituted or monosubstituted phenyl moieties contained in thesegroups, as well as the abovementioned heteroaryl groups may additionallybe substituted at a carbon atom in each case by a fluorine, chlorine orbromine atom, by a trifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group,unless otherwise stated,

[0084] but particularly those compounds wherein

[0085] (i) m denotes the number 0,

[0086] n denotes the number 1 and

[0087] A denotes a methylene group wherein

[0088] one or two hydrogen atoms independently of one another may bereplaced in each case by a C₁₋₃-alkyl group or

[0089] a hydrogen atom may be replaced by the group —(CH₂)_(p)—R_(f),while

[0090] p denotes one of the numbers 0, 1, 2 or 3 and

[0091] R_(f) denotes a hydroxycarbonyl, C₁₋₃-alkoxycarbonyl,N-(C₁₋₃-alkyl)-amino-carbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group or

[0092] (ii) m denotes the number 0,

[0093] n denotes the number 0 and

[0094] A denotes a —CH₂—CH₂— group, or

[0095] (iii) m denotes the number 1,

[0096] n denotes the number 0 and

[0097] A denotes a —CH₂— group,

[0098] the groups R₁ to R₄ are as hereinbefore defined, but R₁ in the 4position is bound to the phenyl group contained in formula I and

[0099] Ar denotes a phenyl group disubstituted by the groups R₅ and R₆,while

[0100] R₅ is bound in the 3 position if R₆ denotes a hydrogen atom, oris bound in the 5 position if R₆ assumes a meaning other than thehydrogen atom, and denotes an amidino group optionally substituted byone or two C₁₋₃-alkyl groups, a hydroxy, C₁₋₆-alkoxy-carbonyl,2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group, or anamino-C₁₋₃-alkyl or C₁₋₃-alkylamino-C₁₋₃-alkyl group and

[0101] R₆ denotes a hydrogen atom or a hydroxy, C₁₋₃-alkoxy,carboxy-C₁₋₃-alkoxy, C₁₋₃-alkoxy-carbonyloxy- orC₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy group bound in the 2 position,

[0102] the stereoisomers and the salts thereof.

[0103] Particularly preferred compounds of general formula I are thosewherein

[0104] (i) m denotes the number 0,

[0105] n denotes the number 1 and

[0106] A denotes a methylene group wherein

[0107] a hydrogen atom may be replaced by a methyl, hydroxycarbonyl,C₁₋₃-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, dimethylaminocarbonyl,pyrrolidin-1-yl-carbonyl, C₁₋₃-alkylaminocarbonylmethyl,N-(hydroxy-carbonyl-methyl)-N-(C₁₋₃-alkyl)-amino-carbonyl-methyl,N-(C₁₋₃-alkoxy-carbonyl-methyl)-N-(C₁₋₃-alkyl)-amino-carbonyl-methyl,hydroxycarbonylmethyl, C₁₋₃-alkoxy-carbonylmethyl ordimethylaminocarbonylmethyl group,

[0108] R₁ is bound in the 4 position of the phenyl group of formula Iand denotes

[0109] a C₅₋₇-cycloalkylamino group which may be substituted at theamino nitrogen atom by a C₁₋₃-alkyl, C₁₋₃-alkylcarbonyl,amino-C₁₋₃-alkylcarbonyl, carboxy-C₁₋₃-alkylcarbonyl orC₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-carbonyl group,

[0110] a 4- to 7-membered cycloalkyleneiminocarbonyl group

[0111] or a 2,5-dihydropyrrol-1-yl-carbonyl group,

[0112] R₂ denotes a hydrogen atom or a C₁₋₃-alkyl, ethenyl, ethynyl,trifluoromethyl or trifluoromethoxy group bound in the 3 position or, ifR₃ denotes a C₁₋₃-alkyl group, in the 5 position of the phenyl group informula I or a chlorine or bromine atom bound in the 3 position,

[0113] R₃ denotes a hydrogen atom or a C₁₋₃-alkyl group bound in the 2position of the phenyl group in formula I,

[0114] R₄ denotes a hydrogen atom and

[0115] Ar denotes a phenyl group disubstituted by the groups R₅ and R₆,while

[0116] R₅ is bound in the 3 position if R₆ denotes a hydrogen atom, oris bound in the 5 position if R₆ assumes a meaning other than thehydrogen atom, and denotes an amidino group optionally substituted by aC₁₋₆-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonylgroup, or a aminomethyl group and

[0117] R₆ denotes a hydrogen atom or a hydroxy orC₁₋₃-alkoxy-carbonyloxy group bound in the 2 position,

[0118] as well as those compounds wherein

[0119] (i) m denotes the number 0,

[0120] n denotes the number 0 and

[0121] A denotes a —CH₂—CH₂— group, or

[0122] (ii) m denotes the number 1,

[0123] n denotes the number 0 and

[0124] A denotes a —CH₂— group,

[0125] R₁ denotes a 4- to 7-membered cycloalkyleneiminocarbonyl or2,5-dihydropyrrol-1-yl-carbonyl group bound in the 4 position of thephenyl group of formula I,

[0126] R₂ denotes a hydrogen atom or a substituent selected fromfluorine, chlorine, bromine, C₁₋₃-alkyl and trifluoromethyl bound in the3 position or, if R₃ denotes a C₁₋₃-alkyl group, bound in the 5 positionof the phenyl group in formula I,

[0127] R₃ denotes a hydrogen atom or a C₁₋₃-alkyl group bound in the 2position of the phenyl group in formula I,

[0128] R₄ denotes a hydrogen atom and

[0129] Ar denotes a phenyl group disubstituted by the groups R₅ and R₆,wherein

[0130] R₅ is bound in the 5 position and denotes an amidino groupoptionally substituted by one or two C₁₋₃-alkyl groups, aC₁₋₆-alkoxy-carbonyl or phenylcarbonyl group and

[0131] R₆ denotes a hydroxy group bound in the 2 position,

[0132] the stereoisomers and the salts thereof.

[0133] The following preferred compounds are mentioned by way ofexample:

[0134] (1)2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine,

[0135] (2)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine,

[0136] (3)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine,

[0137] (4)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0138] (5)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0139] (6)N-(3-carbamimidoyl-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0140] (7)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0141] (8)N-(5-aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0142] (9)2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-aceticacid-N-ethylamide,

[0143] (10)3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-N-ethylamide,

[0144] (11)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxy-carbonyl-propionyl)amino]-benzamide,

[0145] (12)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutylamino)-benzamide,

[0146] (13)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methyl-amino)-benzamide,

[0147] (14)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionyl)amino]-benzamide,

[0148] (15)N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide,

[0149] (16) ethyl2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetate,

[0150] (17)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid,

[0151] (18)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclopentyl-amino]-benzamide,

[0152] (19)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzamide,

[0153] (20)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0154] (21) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0155] (22) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0156] (23) ethyl3-(3-carbamimidoyl-phenyl)-3-{3-methyl-4-[N-(3-amino-propionyl)-N-cyclo-pentyl-amino]-benzoylamino}-propionate,

[0157] (24) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0158] (25) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionate,

[0159] (26) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0160] (27) ethyl 3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0161] (28) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,

[0162] (29)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid,

[0163] (30)3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0164] (31)3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0165] (32)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0166] (33)3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid,

[0167] (34)3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0168] (35)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-methyl-N-(hydroxycarbonylmethyl)-amide,

[0169] (36)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(hydroxycarbonylmethyl)-N-(n-propyl)-amide,

[0170] (37)3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid,

[0171] (38)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid-N,N-dimethylamide,

[0172] (39)N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0173] (40)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid-N,N-dimethylamide,

[0174] (41)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid-N-ethylamide,

[0175] (42)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid-N-ethylamide,

[0176] (43)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(ethoxycarbonylmethyl)-N-(n-propyl)-amide,

[0177] (44)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0178] (45)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0179] (46)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0180] (47) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,

[0181] (48)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0182] (49)3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0183] (50) ethyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,

[0184] (51) ethyl3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,

[0185] (52) n-propyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,

[0186] (53) ethyl3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,

[0187] (54)N-{5-[N-(n-hexyloxycarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0188] (55)N-{5-[N-(phenylcarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0189] (56)N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamideand

[0190] (57)N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,

[0191] wherein any amidino group present may additionally be substitutedby a C₁₋₆-alkoxy-carbonyl or phenylcarbonyl group, and the saltsthereof.

[0192] According to the invention, the compounds of general formula Iare obtained by methods known per se, e.g. by the following processes:

[0193] a) In order to prepare a compound of general formula I wherein

[0194] (i) m denotes the number 0, n denotes the number 1 and A denotesa straight-chain C₁₋₃-alkylene group wherein

[0195] one or two hydrogen atoms independently of one another may bereplaced in each case by a C₁₋₃-alkyl group or

[0196] a hydrogen atom may be replaced by the group —(CH₂)_(p)—R_(f),while p and R_(f) are as hereinbefore defined, or

[0197] (ii) m and n each denote the number 1 and A denotes a bond and

[0198] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes an amidino group:

[0199] acylating a compound of general formula

H—NR₄—A—Ar  (II),

[0200] wherein R₄ is as hereinbefore defined,

[0201] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group or a hydrogen atom may be replaced by the group—(CH₂)_(p)—R_(f), while p and R_(f) are as hereinbefore defined, ordenotes a bond and

[0202] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₅ denotes a cyano group and R₆ and R₇ are ashereinbefore defined,

[0203] with a carboxylic acid or a reactive carboxylic acid derivativeof general formula

[0204] wherein m denotes the number 0 or 1, X denotes a hydroxy orC₁₋₄-alkoxy group or a chlorine atom and R₁ to R₃ are as hereinbeforedefined, or with the reactive derivatives thereof and subsequentlyconverting the cyano compound thus obtained into an amidino compound.

[0205] The acylation is conveniently carried out with a correspondinghalide or anhydride in a solvent such as methylene chloride, chloroform,carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene,acetonitrile, dimethylformamide, sodium hydroxide solution or sulpholaneoptionally in the presence of an inorganic or organic base attemperatures between −20 and 200° C., but preferably at temperaturesbetween −10 and 160° C.

[0206] The acylation may however also be carried out with the free acidoptionally in the presence of an acid-activating agent or a dehydratingagent, e.g. in the presence of isobutyl chloroformate, thionyl chloride,trimethylchlorosilane, hydrogen chloride, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole, N,N′-carbonyldiimidazole,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-methylmorpholine,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate/N-ethyldiisopropylamine, N,N′-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, at temperatures between −20 and200° C., but preferably at temperatures between −10 and 160° C.

[0207] The subsequent conversion of the cyano group into an amidinogroup takes place as described in process e).

[0208] b) In order to prepare a compound of general formula I wherein mdenotes the number 0 or

[0209] n denotes the number 0,

[0210] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group, and

[0211] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes an amidino group:

[0212] alkylating a compound of general formula

[0213] wherein R₁ to R₄ are as hereinbefore defined and m denotes thenumber 0 or 1, with a compound of general formula

Z₁—A—Ar  (V),

[0214] wherein A denotes a straight-chain C₁₋₃-alkylene group whereinone or two hydrogen atoms independently of one another may be replacedin each case by a C₁₋₃-alkyl group,

[0215] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes a cyano group,

[0216] and Z₁ denotes a leaving group such as a halogen atom or asulphonyloxy group, e.g. a chlorine, bromine or iodine atom or atrifluoromethylsulphonyloxy group, and subsequently converting the cyanocompound thus obtained into an amidino compound.

[0217] The alkylation is optionally carried out in a solvent or mixtureof solvents such as methylene chloride, dimethylformamide, benzene,toluene, chlorobenzene, tetra-hydrofuran, benzene/tetrahydrofuran,dioxan, dimethylsulphoxide or sulpholane with an alkylating agent suchas a corresponding halide or sulphonic acid ester, e.g. with methyliodide, ethyl bromide, dimethylsulphate or benzyl chloride, optionallyin the presence of a tertiary organic base or in the presence of aninorganic base, conveniently at temperatures between 0 and 150° C.,preferably at temperatures between 0 and 100° C.

[0218] The subsequent conversion of the cyano group into an amidinogroup is carried out as described in process e).

[0219] c) In order to prepare a compound of general formula I wherein

[0220] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes an amidino group,

[0221] m denotes the number 1, n denotes the number 0 and

[0222] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group, or m denotes the number 2, n denotes the number 0and A denotes a bond:

[0223] alkylating a compound of general formula

HNR₄ —A—Ar  (II′),

[0224] wherein R₄ is as hereinbefore defined,

[0225] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group, or denotes a bond, and

[0226] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes a cyano group,

[0227] with a compound of general formula

[0228] wherein R₁ to R₃ are as hereinbefore defined, m denotes thenumber 1 or 2 and Z₂ denotes a leaving group such as a halogen atom or asulphonyloxy group, e.g. a chlorine, bromine or iodine atom or atrifluoromethylsulphonyloxy group, and subsequently converting theresulting cyano compound into an amidino compound.

[0229] The alkylation is optionally carried out in a solvent or mixtureof solvents such as methylene chloride, dimethylformamide, benzene,toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran,dioxan, dimethylsulphoxide or sulpholane with an alkylating agent suchas a corresponding halide or sulphonic acid ester, e.g. with methyliodide, ethyl bromide, dimethylsulphate or benzyl chloride, optionallyin the presence of a tertiary organic base or in the presence of aninorganic base conveniently at temperatures between 0 and 150° C.,preferably at temperatures between 0 and 100° C.

[0230] The subsequent conversion of the cyano group into an amidinogroup is carried out as described in process e).

[0231] d) In order to prepare a compound of general formula I wherein

[0232] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes an amidino group,

[0233] m denotes the number 0 or 1, n denotes the number 0 and

[0234] A denotes a straight-chain C₁₋₃-alkylene group wherein one or twohydrogen atoms independently of one another may be replaced in each caseby a C₁₋₃-alkyl group, or

[0235] m denotes the number 2, n denotes the number 0 and A denotes abond: reductive alkylation of an amine of general formula

[0236] wherein R₁ to R₄ are as hereinbefore defined and m denotes thenumber 0, 1 or 2, with an aldehyde of general formula

[0237] wherein A denotes a straight-chain C₁₋₃-alkylene group whereinone or two hydrogen atoms independently of one another may be replacedin each case by a C₁₋₃-alkyl group, or denotes a bond, and

[0238] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes a cyano group, and subsequently converting the resulting cyanocompound into an amidino compound.

[0239] The reductive alkylation is however preferably carried out in thepresence of a complex metal hydride such as sodium borohydride, lithiumborohydride, sodium cyanoborohydride, zinc borohydride, sodiumtriacetoxyborohydride or borane/pyridine conveniently at a pH of 1-7optionally in the presence of a dehydrating agent such as molecularsieve or titanium-IV-isopropoxide and at ambient temperature or withhydrogen in the presence of a hydrogenation catalyst, e.g. in thepresence of palladium/charcoal, at a hydrogen pressure of 1 to 5 bar,preferably at temperatures between 20° C. and the boiling temperature ofthe solvent used. It may also be advantageous during the reaction ifreactive groups are protected during the reaction by conventionalprotecting groups which are cleaved again by conventional methods afterthe reaction.

[0240] The subsequent conversion of the cyano group into an amidinogroup is carried out as described in process e).

[0241] e) In order to prepare a compound of general formula I wherein Ardenotes a phenyl or naphthyl group substituted by the groups R₅, R₆ andR₇, while R₆ and R₇ are as hereinbefore defined and R₅ denotes anamidino group optionally substituted by one or two C₁₋₃-alkyl groups:

[0242] reacting a compound of general formula

[0243] optionally formed in the reaction mixture,

[0244] wherein

[0245] R₁ to R₄, m, n and A are as hereinbefore defined, Ar denotes aphenyl or naphthyl group substituted by the groups R₆ and R₇, while R₆and R₇ are as hereinbefore defined, and Z₃ denotes an alkoxy or aralkoxygroup such as the methoxy, ethoxy, n-propoxy, iso-propoxy or benzyloxygroup or an alkylthio or aralkylthio group such as the methylthio,ethylthio, n-propylthio or benzylthio group, with an amine of generalformula

H—R₈NR₉,  (IX)

[0246] wherein

[0247] R₈ and R₉, which may be identical or different, each denote ahydrogen atom or a C₁₋₃-alkyl group, or with the salts thereof.

[0248] The reaction is conveniently carried out in a solvent such asmethanol, ethanol, n-propanol, tetrahydrofuran or dioxan at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 80° C.,with an amine of general formula IX or with a corresponding acidaddition salt such as for example ammonium carbonate or ammoniumacetate.

[0249] A compound of general formula VIII is obtained for example byreacting a corresponding cyano compound with a corresponding alcoholsuch as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol inthe presence of an acid such as hydrochloric acid or by reacting acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetrafluoroborate in a solvent such as methylenechloride, tetrahydrofuran or dioxan at temperatures between 0 and 50°C., but preferably at 20° C., or a corresponding nitrile with hydrogensulphide conveniently in a solvent such as pyridine or dimethylformamideand in the presence of a base such as triethylamine and subsequentlyalkylating the thioamide formed with a corresponding alkyl or aralkylhalide.

[0250] f) In order to prepare a compound of general formula I wherein Ardenotes a phenyl or naphthyl group substituted by the groups R₅, R₆ andR₇, while R₆ and R₇ are as hereinbefore defined and R₅ denotes anaminomethyl, C₁₋₃-alkylaminomethyl or di-(C₁₋₃-alkyl)aminomethyl group:

[0251] Catalytic hydrogenation of a compound of general formula

[0252] wherein

[0253] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, R₁ to R₄, R₆, R₇, A, m and n are as hereinbefore definedand R₅ denotes a cyano group, and optionally subsequent alkylation witha compound of formula

R₁₀—Z₄  (X),

[0254] wherein R₁₀ denotes a C₁₋₃-alkyl group and Z₄ denotes a leavinggroup such as a halogen atom or a sulphonyloxy group, e.g. a chlorine,bromine or iodine atom or a trifluoromethyl-sulphonyloxy group.

[0255] The catalytic hydrogenation is carried out with hydrogen in thepresence of a catalyst such as palladium/charcoal, platinum in a solventsuch as methanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar, or for example withRaney nickel preferably in methanolic ammonia solution.

[0256] The alkylation which optionally follows is conveniently carriedout in a solvent or mixture of solvents such as methylene chloride,dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran, dioxan, dimethylsulphoxide or sulpholane withan alkylating agent such as a corresponding halide or sulphonic acidester, e.g. with methyl iodide, ethyl bromide, dimethylsulphate orbenzyl chloride, optionally in the presence of a tertiary organic baseor in the presence of an inorganic base conveniently at temperaturesbetween 0 and 150° C., preferably at temperatures between 0 and 100° C.

[0257] g) In order to prepare a compound of general formula I wherein

[0258] m denotes the number 0, n denotes the number 0, A denotes astraight-chain C₁₋₃-alkylene group wherein one or two hydrogen atomsindependently of one another may be replaced in each case by aC₁₋₃-alkyl group, and

[0259] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes an amidino group:

[0260] coupling a compound of general formula

[0261] wherein

[0262] R₁ to R₃ are as hereinbefore defined and Z₅ denotes a leavinggroup such as a halogen atom or a sulphonyloxy group, e.g. a chlorine,bromine or iodine atom or a trifluoromethylsulphonyloxy group,

[0263] with a compound of general formula

HNR₄ —A—Ar  (II″),

[0264] wherein R₄ is as hereinbefore defined, A denotes a straight-chainC₁₋₃-alkylene group wherein one or two hydrogen atoms independently ofone another may be replaced in each case by a C₁₋₃-alkyl group, and

[0265] Ar denotes a phenyl or naphthyl group substituted by the groupsR₅, R₆ and R₇, while R₆ and R₇ are as hereinbefore defined and R₅denotes a cyano group, and subsequently converting the resulting cyanocompound into an amidino compound.

[0266] The coupling reaction is conveniently carried out in a solventsuch as toluene, dioxan, dimethoxyethane or tetrahydrofuran using asuitable catalyst, for examplebis-(tri-o-tolylphosphine)-palladium-(II)-chloride,tris-(dibenzylideneacetone)-dipalladium(0)/tris-o-tolylphosphine,tris-(dibenzylideneacetone)-dipalladium(0)/tris-(2-furyl)phosphan,tris-(dibenzylideneacetone)-dipalladium(1)/2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl,tetrakis-(triphenylphosphine)-palladium(0), 1,1′-bis-(diphenylphosphino)-ferrocene-palladium-dichloride orpalladium-II-acetate/1,3-bis-(triphenylphosphino)-propane, preferably inthe presence of a base such as sodium-tert.butoxide,bis-(trimethylsilyl)-lithium amide, potassium carbonate, caesiumcarbonate or triethylamine at a temperature between 0 and 150° C.,preferably 20 to 100° C.

[0267] The subsequent conversion of the cyano group into an amidinogroup is carried out as described in process e).

[0268] If according to the invention a compound of general formula I isobtained which contains an amino or imino group, this may subsequentlybe converted with a corresponding acyl derivative into a correspondingacyl compound of general formula I and/or

[0269] if a compound of general formula I is obtained which contains anesterified carboxy group, this may be converted by hydrolysis into acorresponding carboxylic acid of general formula I and/or

[0270] if a compound of general formula I is obtained which contains acarboxy group, this may subsequently be converted by esterification intoa corresponding ester.

[0271] The subsequent acylation is conveniently carried out with acorresponding halide or anhydride in a solvent such as methylenechloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,dioxan, benzene, toluene, acetonitrile or sulpholane optionally in thepresence of an inorganic or organic base at temperatures between −20 and200° C., but preferably at temperatures between −10 and 160° C. This mayhowever also be carried out with the free acid, optionally in thepresence of an acid-activating agent or a dehydrating agent, e.g. in thepresence of isobutyl chloroformate, thionylchloride,trimethylchlorosilane, hydrogen chloride, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole, N,N′-carbonyldiimidazole orN,N′-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, attemperatures between −20 and 200° C., but preferably at temperaturesbetween −10 and 160° C.

[0272] The subsequent hydrolysis is conveniently carried out either inthe presence of an acid such as hydrochloric acid, sulphuric acid,phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acidor mixtures thereof or in the presence of a base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, water/methanol, water/ethanol, water/isopropanol,methanol, ethanol, water/tetrahydrofuran or water/dioxan and thesubsequent decarboxylation in the presence of an acid as hereinbeforedescribed at temperatures between −10 and 120° C., e.g. at temperaturesbetween ambient temperature and the boiling temperature of the reactionmixture.

[0273] The subsequent esterification is carried out with a correspondingalcohol, conveniently in a solvent or mixture of solvents such asmethylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxan, but preferably in an excess of thealcohol used, optionally in the presence of an acid such as hydrochloricacid or in the presence of a dehydrating agent, e.g. in the presence ofisobutyl chloroformate, thionyl chloride, trimethylchlorosilane,hydrochloric acid, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-carbonyldiimidazole or N,N′-thionyldiimidazole,triphenylphosphine/carbon tetrachloride or triphenyl-phosphine/diethylazodicarboxylate, optionally in the presence of a base such as potassiumcarbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine,conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 80° C., or with a corresponding halide in asolvent such as methylene chloride, tetrahydrofuran, dioxan,dimethylsulphoxide, dimethylformamide or acetone optionally in thepresence of a reaction accelerator such as sodium or potassium iodideand preferably in the presence of a base such as sodium carbonate orpotassium carbonate or in the presence of a tertiary organic base suchas N-ethyl-diisopropylamine or N-methyl-morpholine, which may alsosimultaneously serve as the solvent, or optionally in the presence ofsilver carbonate or silver oxide at temperatures between −30 and 100°C., but preferably at temperatures between −10 and 80° C.

[0274] In the reactions described hereinbefore, any reactive groupspresent such as hydroxy, carboxy, amino, alkylamino or imino groups maybe protected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

[0275] For example, a protecting group for a hydroxy group may be amethoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl,benzyl or tetrahydropyranyl group,

[0276] protecting groups for a carboxy group may be a trimethylsilyl,methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and

[0277] protecting groups for an amino, alkylamino or imino group may bean acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl group.

[0278] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, acetic acid/water, tetrahydrofuran/water ordioxan/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as lithium hydroxide, sodium hydroxide or potassiumhydroxide or by ether splitting, e.g. in the presence ofiodotrimethylsilane, at temperatures between 0 and 100° C., preferablyat temperatures between 10 and 50° C.

[0279] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example, hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 50° C., but preferably at ambient temperature, and at a hydrogenpressure of 1 to 7 bar, but preferably 3 to 5 bar.

[0280] A methoxybenzyl group may also be cleaved in the presence of aoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesbetween 0 and 50° C., but preferably at ambient temperature.

[0281] A methoxy group is conveniently cleaved in the presence of borontribromide in a solvent such as methylene chloride at temperaturesbetween −35 and −25° C.

[0282] A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisole.

[0283] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid, optionally using a solvent such as methylene chloride, dioxan orether.

[0284] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxan at temperatures between 20 and 50° C.

[0285] An allyloxycarbonyl group is cleaved by treating with a catalyticamount of tetrakis-(triphenylphosphine)-palladium(O), preferably in asolvent such as tetrahydrofuran and preferably in the presence of anexcess of a base such as morpholine or 1,3-dimedone at temperaturesbetween 0 and 100° C., preferably at ambient temperature and under inertgas, or by treating with a catalytic amount oftris-(triphenylphosphine)-rhodium(I)chloride in a solvent such asaqueous ethanol and optionally in the presence of a base such as1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C.

[0286] The compounds of general formulae II to XI used as startingmaterials, some of which are known from the literature, are obtained bymethods known from the literature and their preparation is alsodescribed in the Examples.

[0287] The chemistry of the compounds of general formula II, II′, II″ IVand IV′ is described, for example, by Schröter in StickstoffverbindungenII, pages 341-730, Methoden der organischen Chemie (Houben-Weyl), 4^(th)edition, Verlag Thieme, Stuttgart 1957. The preparation of carboxylicacid derivatives of general formula III is described in Methoden derorganischen Chemie (Houben-Weyl), Volume E5, Carbonsäuren undCarbonsäurederivate, 4^(th) edition, Verlag Thieme, Stuttgart 1985.

[0288] Moreover, the compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers.

[0289] Thus, for example, the compounds of general formula I obtainedwhich occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical enantiomers and compoundsof general formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0290] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

[0291] Furthermore, the compounds of formula I may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

[0292] Moreover, if the new compounds of formula I contain a carboxygroup, they may subsequently, if desired, be converted into the saltsthereof with inorganic or organic bases, particularly for pharmaceuticaluse into the physiologically acceptable salts thereof. Suitable basesfor this purpose include for example sodium hydroxide, potassiumhydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

[0293] As already mentioned, the new compounds of general formula I andthe salts thereof have valuable properties. Thus, the compounds ofgeneral formula I wherein Ar denotes a phenyl or naphthyl groupsubstituted by the groups R₅, R₆ and R₇ and R₅ denotes a cyano group arevaluable intermediates for preparing the corresponding compounds ofgeneral formula I wherein R₅ denotes an amidino group optionallysubstituted by one or two C₁₋₃-alkyl groups. The compounds of generalformula I with the exception of those compounds wherein Ar denotes aphenyl or naphthyl group substituted by the groups R₅, R₆ and R₇ and R₅denotes a cyano group, as well as the tautomers, the stereoisomers andthe physiologically acceptable salts thereof, have valuablepharmacological properties, particularly an antithrombotic activitywhich is preferably based on an effect on thrombin or factor Xa, on aprolonging effect on aPTT time and on an inhibitory effect on relatedserine proteases such as e.g. trypsin, urokinase, factor VIIa, factorIX, factor XI and factor XII.

[0294] For example, the compounds

[0295] (1)2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine-hydrochloride,

[0296] (2)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride,

[0297] (3)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxy-carbonylpropionyl)amino]-benzamide-hydrochloride,

[0298] (4)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamideand

[0299] (5)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid,

[0300] were investigated for their effect on the inhibition of factor Xaas follows:

[0301] Method:

[0302] Enzyme-kinetic measurement with chromogenic substrate. Thequantity of anp-nitroaniline (pNA) released from the colourlesschromogenic substrate by human factor Xa is determined photometricallyat 405 nm. It is proportional to the activity of the enzyme used. Theinhibition of the enzyme activity by the test substance I (in relationto the solvent control) is determined at various concentrations of testsubstance and from this the IC₅₀ is calculated, as the concentrationwhich inhibits the factor Xa used by 50%.

[0303] Material:

[0304] Tris(hydroxymethyl)-aminomethane buffer (100 mmol) and sodiumchloride (150 mMol), pH 8.0

[0305] Factor Xa (Roche), spec. activity: 10 U/0.5 ml, finalconcentration: 0.175 U/ml for each reaction mixture

[0306] Substrate Chromozym X (Roche), final concentration: 200 μMol/lfor each reaction mixture

[0307] Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1,0.03, 0.01, 0.003, 0.001 μMol/l

[0308] Procedure:

[0309] 10 μl of a 23.5-times concentrated starting solution of the testsubstance or solvent (control), 175 μl oftris(hydroxymethyl)-aminomethane buffer and 25 μl of a 1.65 U/ml FactorXa working solution are incubated for 10 minutes at 37° C. After theaddition of 25 μl of Chromozym X working solution (1.88 μMol/l) thesample is measured in a photometer (SpectraMax 250) at 405 nm for 150seconds at 37° C.

[0310] Evaluation:

[0311] 1. Determining the maximum increase (deltaOD/minutes) over 3measuring points.

[0312] 2. Determining the % inhibition based on the solvent control.

[0313] 3. Plotting a dosage/activity curve (% inhibition vs substanceconcentration).

[0314] 4. Determining the IC₅₀ by interpolating the X value (substanceconcentration) of the dosage/activity curve at Y=50% inhibition.

[0315] The following Table shows the results obtained: Inhibition offactor Xa Substance (IC₅₀ in μM) (1) 0.084 (2) 0.014 (3) 0.075 (4) 0.01(5) 0.031

[0316] The compounds prepared according to the invention are welltolerated, as no toxic side effects could be observed at therapeuticdoses.

[0317] In view of their pharmacological properties the new compounds,with the exception of those compounds wherein Ar denotes a phenyl ornaphthyl group substituted by the groups R₅, R₆ and R₇, and R₅ denotes acyano group, and the physiologically acceptable salts thereof aresuitable for the prevention and treatment of venous and arterialthrombotic diseases, such as for example the treatment of deep leg veinthrombosis, for preventing reocclusions after bypass operations orangioplasty (PT(C)A), and occlusion in peripheral arterial diseases suchas pulmonary embolism, disseminated intravascular coagulation, forpreventing coronary thrombosis, stroke and the occlusion of shunts. Inaddition, the compounds according to the invention are suitable forantithrombotic support in thrombolytic treatment, such as for examplewith alteplase, reteplase, tenecteplase, staphylokinase orstreptokinase, for preventing long-term restenosis after PT(C)A, for theprevention and treatment of ischaemic incidents in patients withunstable angina or non-transmural cardiac infarct, for preventingmetastasis and the growth of clot-dependent tumours and fibrin-dependentinflammatory processes, e.g. in the treatment of pulmonary fibrosis, forthe prevention and treatment of rheumatoid arthritis, for preventingfibrin-dependent tissue adhesions and/or the formation of scar tissueand for promoting wound healing processes. The new compounds and thephysiologically acceptable salts thereof may be used therapeutically inconjunction with inhibitors of platelet aggregation such as fibrinogenreceptor antagonists (e.g. abciximab, eptifibatide, tirofiban), withinhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine),with P₂T receptor antagonists (e.g. cangrelor) or with combinedthromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

[0318] The dosage required to achieve such an effect is appropriately 3to 30 mg/kg, preferably 1 to 10 mg/kg by intravenous route, and 5 to 50mg/kg, preferably 3 to 30 mg/kg by oral route, in each case administered1 to 4 times a day. For this purpose, the compounds of formula Iprepared according to the invention may be formulated, optionallytogether with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethylene glycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substancessuch as hard fat or suitable mixtures thereof, to produce conventionalgalenic preparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

[0319] The Examples which follow are intended to illustrate theinvention:

EXAMPLE 1

[0320]2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine-hydrochloride

[0321] a. 2-methyl-4-bromo-benzoic acid-pyrrolidinamide

[0322] 35 g (0.163 mol) of 2-methyl-4-bromo-benzoic acid are dissolvedin 1 l tetrahydrofuran and 100 ml water and combined with 57.8 g (0.18mol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate, 22.0 g (0.163 mol) of N-hydroxybenzotriazole and 62.7ml (0.36 mol) of ethyl-dicyclohexylamine. After 10 minutes at ambienttemperature 13.9 ml (0.167 mol) of pyrrolidine are added. The reactionmixture is stirred for 24 hours and evaporated down. The residue iscombined with 5% saline solution/methylene chloride and extracted. Theaqueous phase is extracted three times with methylene chloride, thecombined organic phases are dried and evaporated down. The residue ispurified on silica gel, eluting with methylene chloride plus ethanol(0-3%). The uniform fractions are combined and evaporated down.

[0323] Yield: 42 g (77% of theoretical),

[0324] R_(f) value: 0.45 (dichloromethane/ethanol=95:5)

[0325] b. N-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-acetamide

[0326] 1.9 g (9.8 mmol) of N-[2-(2-methoxy-phenyl)-ethyl]-acetamide aredissolved in 50 ml acetonitrile and after the addition of 2 g (11 mmol)of N-bromosuccinimide stirred for 4 hours at ambient temperature. Thenthe solvent is distilled off, the residue is stirred withdichloromethane and suction filtered. The mother liquor is evaporateddown and chromatographed on silica gel, eluting withdichloromethane/methanol/ammonia (50:0.9:0.1).

[0327] Yield: 2.6 g (99% of theoretical),

[0328] R_(f) value: 0.47 (silica gel;dichloromethane/methanol/ammonia=24:0.9:0.1)

[0329] c. N-[2-(5-cyano-2-methoxy-phenyl)-ethyl]-acetamide

[0330] 12.5 g (45.9 mmol) ofN-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-acetamide are dissolved in 50 mldimethylformamide and after the addition of 8.2 g (91 mmol) of coppercyanide, 577 mg (0.5 mmol) of tetrakis-triphenylphosphine-palladium-(0)and 11.6 g aluminium oxide stirred for 20 hours under a nitrogenatmosphere at 140° C. The warm suspension is suction filtered and themother liquor is evaporated down. The residue is chromatographed onsilica gel, eluting with dichloromethane/ethanol (0-3%).

[0331] Yield: 4.9 g (49% of theoretical),

[0332] R_(f) value: 0.35 (silica gel;dichloromethane/methanol/ammonia=19:0.9:0.1)

[0333] d. (5-cyano-2-methoxy-phenyl)-ethylamine

[0334] 4.9 g (22.4 mmol) ofN-[2-(5-cyano-2-methoxy-phenyl)-ethyl]-acetamide are dissolved in 20 mlglacial acetic acid and after the addition of 60 ml of 3 molarhydrochloric acid refluxed for 15 hours. Then the solvent is distilledoff, the residue is triturated in acetone and suction filtered. Thecrude product is dissolved in water, made alkaline with conc. ammoniaand extracted with ethyl acetate. The organic phase is dried andevaporated down.

[0335] Yield: 2.6 g (66% of theoretical),

[0336] R_(f) value: 0.51 (silica gel;dichloromethane/methanol/ammonia=4:0.9:0.1)

[0337] e.2-(5-cyano-2-methoxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine

[0338] A solution of 2.0 g (6.7 mmol) of 2-methyl-4-bromo-benzoicacid-pyrrolidinamide and 1.9 g (8.5 mmol) of(5-cyano-2-methoxy-phenyl)-ethylamine in 75 ml toluene is combined undera nitrogen atmosphere with 5.7 g (17.5 mmol) of caesium carbonate, 120mg (0.27 mmol) of palladium-I1-acetate and 240 mg (0.385 mmol) of2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (BINAP) and heated to 130°C. for 18 hours. After cooling the reaction mixture is stirred with icewater and extracted with methylene chloride. The organic phase is washedwith water, dried over magnesium sulphate and evaporated down. The crudeproduct is purified on silica gel, eluting with methylenechloride/methanol/ammonia (1/0/0; 50/0.9/0.1 and 33/0.9/0.1).

[0339] Yield: 0.9 g (37% of theoretical),

[0340] R_(f) value: 0.71 (silica gel;dichloromethane/methanol/ammonia=9:0.9:0.1)

[0341] f.2-(5-cyano-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]ethylamine

[0342] 0.5 g (1.3 mmol) of2-(5-cyano-2-methoxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamineare dissolved in 40 ml dichloromethane and combined with 7 ml (7 mmol)of boron tribromide (1 M solution in dichloromethane) at −45 to −25° C.The reaction mixture is stirred for 20 hours at ambient temperature,combined with ice and conc. ammonia and extracted withdichloromethane/methanol (19:1). The combined organic extracts areevaporated down and chromatographed on silica gel, eluting withdichloromethane/ethanol (0-3%).

[0343] Yield: 0.2 g (46% of theoretical),

[0344] R_(f) value: 0.42 (silica gel; ethylacetate/toluene/ammonia=9:0.9:0.1)

[0345] g.2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine-hydrochloride

[0346] 0.2 g (0.63 mmol) of2-(5-cyano-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamineare dissolved in ethanolic hydrochloric acid and stirred for 4.75 hoursat ambient temperature. The reaction mixture is evaporated down, takenup in 25 ml ethanol and combined with 0.9 g (9.5 mmol) of ammoniumcarbonate. After 18 hours at ambient temperature the undissolvedmaterial is filtered off and the filtrate evaporated down. The residueis triturated with ether, filtered, washed with ether and dried.

[0347] Yield: 0.2 g (87% of theoretical),

[0348] R_(f) value: 0.58 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=1:2)

[0349] C₂₁H₂₆N₄O₂xHCl (366.47/402.93)

[0350] Mass spectrum: (M+H)⁺=367 (M+Cl)⁻=401/03 (Cl)

EXAMPLE 2

[0351]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine-hydrochloride

[0352] a. 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile

[0353] Prepared analogously to Example 1.c. from2-methyl-4-bromo-benzoic acid-pyrrolidinamide, copper cyanide,tetrakis-triphenylphosphine-palladium-(0) and aluminium oxide indimethylformamide.

[0354] Yield: 39% of theoretical,

[0355] R_(f) value: 0.22 (silica gel; cyclohexane/ethyl acetate=1:1)

[0356] b. 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine

[0357] 2.3 g 3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile aredissolved in 75 ml ethanolic ammonia and after the addition of 0.4 gRaney nickel hydrogenated for 3 hours at 70° C. with hydrogen. Then thecatalyst is filtered off and the filtrate is evaporated down.

[0358] Yield: 2.3 g (100% of theoretical),

[0359] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

[0360] c.N-(5-cyano-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine

[0361] A solution of 1.1 g (5 mmol) of3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine in 10 ml methanol iscombined with 0.3 ml (5 mmol) of glacial acetic acid and 0.2 g (3.5mmol) of sodium cyanoborohydride. After 15 minutes 0.5 g (3.4 mmol) of3-formyl-4-hydroxy-benzonitrile are added. The reaction mixture isstirred for 2 hours at ambient temperature and combined with ice andhydrochloric acid. By adding conc. ammonia the solution is adjusted topH 8 and extracted with dichloromethane. The organic phase is evaporateddown and chromatographed over silica gel, eluting with ethyl acetate.

[0362] Yield: 0.6 g (32% of theoretical),

[0363] R_(f) value: 0.33 (silica gel; dichloromethane/ethanol=19:1)

[0364] d.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine-hydrochloride

[0365] Prepared analogously to Example 1.g. fromN-(5-cyano-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamineand hydrochloric acid/ammonium carbonate in ethanol.

[0366] Yield: 98% of theoretical,

[0367] R_(f) value: 0.66 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=1:1)

[0368] C₂₁H₂₆N₄O₂xHCl (366.47/402.93)

[0369] Mass spectrum: (M+H)⁺=367 (M−H)⁻=365 (M+Cl)⁻=401/03 (Cl)

[0370] The following compound is prepared analogously to Example 2:

[0371] (1)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine-dihydrochloride

[0372] Yield: 27% of theoretical,

[0373] R_(f) value: 0.6 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0374] C₂₂H₂₈N₄O₂x2HCl (380.49/453.41)

[0375] Mass spectrum: (M+H)⁺=381

EXAMPLE 3

[0376]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0377] a. 4-benzyloxy-3-hydroxymethyl-benzonitrile

[0378] A solution of 1.7 g (6.9 mmol) of4-benzyloxy-3-formyl-benzonitrile in 10 ml tetrahydrofuran at 5-10° C.is added dropwise to a solution of 0.15 g (3.9 mmol) of sodiumborohydride in 20 ml tetrahydrofuran. After 1.5 hours at 110° C. thesolvent is distilled off. The residue is combined with 0.5 N sodiumhydroxide solution and extracted with ethyl acetate. The organic phaseis dried, evaporated down and crystallised with ether/petroleum ether.

[0379] Yield: 1.5 g (91% of theoretical),

[0380] R_(f) value: 0.2 (silica gel; petroleum ether/ethyl acetate=8:2)

[0381] b.4-benzyloxy-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-methyl-benzonitrile

[0382] A solution of 2.6 g (15 mmol) of diethyl azodicarboxylate in 5 mltetrahydrofuran is added dropwise at ambient temperature to a solutionof 0.9 g (6.2 mmol) of phthalimide potassium salt, 1.5 g (6.2 mmol) of4-benzyloxy-3-hydroxymethyl-benzonitrile and 3.9 g (15 mmol) oftriphenylphosphine in 50 ml tetrahydrofuran, while the temperature risesto 42° C. After 24 hours the solvent is distilled off, the residue istaken up in sodium chloride solution/ethyl acetate and extracted withethyl acetate. The combined organic extracts are dried andchromatographed on silica gel, eluting with petroleum ether/ethylacetate (10:0, 9:1 and 8:2).

[0383] Yield: 0.7 g (31% of theoretical),

[0384] R_(f) value: 0.45 (silica gel; petroleum ether/ethyl acetate=7:3)

[0385] c. 4-benzyloxy-3-aminomethyl-benzonitrile

[0386] 0.7 g (1.9 mmol) of4-benzyloxy-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-methyl-benzonitrileare dissolved in 20 ml isopropanol and refluxed for 30 minutes with theaddition of 1.5 ml of hydrazine hydrate. Then the reaction solution isevaporated down, the residue is stirred with ice water, suction filteredand dried.

[0387] Yield: 0.3 g (71% of theoretical),

[0388] R_(f) value: 0.1 (silica gel; petroleum ether/ethyl acetate=1:1)

[0389] d. 3-methyl-4-(pyrrolidin-1-carbonyl)-benzoic acid

[0390] 26.8 g (0.1 mol) of3-methyl-4-(pyrrolidin-1-carbonyl)-bromobenzene, 11.9 ml (0.13 mol) ofn-butanol, 1 g (0.004 mol) of palladium-I1-acetate, 4.2 g (0.016 mol) oftri-phenylphosphine and 15.5 ml (0.12 mol) of N-ethyl-diisopropylamineare placed in a steel bomb and after the addition of carbon monoxideheated for 50 hours to 100° C. After cooling and evaporating off thecarbon monoxide the reaction solution is stirred into ice water andextracted with ethyl acetate. The organic phase is dried and evaporateddown. The residue is taken up in sodium hydrogen carbonate solution andethyl acetate, the aqueous phase is adjusted to pH 4 with hydrochloricacid and extracted with ethyl acetate. The organic phases are dried andevaporated down.

[0391] Yield: 0.8 g (3.4% of theoretical),

[0392] R_(f) value: 0.4 (silica gel; dichloromethane/ethanol=19:1)

[0393] e.N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0394] Prepared analogously to Example 1.a. from3-methyl-4-(pyrrolidin-1-carbonyl)-benzoic acid,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,N-methylmorpholine and 4-benzyloxy-3-aminomethyl-benzonitrile indimethylformamide.

[0395] Yield: 93% of theoretical,

[0396] R_(f) value: 0.5 (silica gel; dichloromethane/ethanol=9:1)

[0397] f.N-(5-carbamimidoyl-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0398] Prepared analogously to Example 1.g. fromN-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochlorideand hydrochloric acid/ammonium carbonate in ethanol.

[0399] Yield: 0.3 g (77% of theoretical),

[0400] R_(f) value: 0.3 (silica gel; dichloromethane/ethanol/glacialacetic acid=8:2+1% glacial acetic acid)

[0401] g.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0402] 0.3 g (0.5 mmol) ofN-(5-carbamimidoyl-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochlorideare dissolved in 50 ml methanol and after the addition of 200 mgpalladium on activated charcoal (10%) hydrogenated with 5 atmospheres ofhydrogen at ambient temperature. Then the catalyst is filtered off, thefiltrate is evaporated down and triturated with petroleum ether/ether(1:1).

[0403] Yield: 120 mg (58% of theoretical),

[0404] C₂₁H₂₄N₄O₃xHCl (380.45/416.91)

[0405] Mass spectrum: (M+H)⁺=381 (M−H)⁻=379

[0406] The following compounds are prepared analogously to Example 3:

[0407](1)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0408] Yield: 81% of theoretical,

[0409] R_(f) value: 0.55 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0410] C₂₂H₂₆N₄O₃xHCl (394.48/430.94)

[0411] Mass spectrum: (M+H)⁺=395 (M−H)⁻=393 (M+Cl)⁻=429/31 (Cl)

[0412] (2)N-(3-carbamimidoyl-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0413] Yield: 88% of theoretical,

[0414] R_(f) value: 0.53 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0415] C₂₁H₂₅N₄O₂xHCl (364.45/400.91)

[0416] Mass spectrum: (M+H)⁺=365 (M+Cl)⁻=399/01 (Cl)

[0417] (3)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0418] Yield: 87% of theoretical,

[0419] R_(f) value: 0.7 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:8)

[0420] C₂₁H₂₁F₃N₄O₃xHCl (434.42/470.88)

[0421] Mass spectrum: (M+H)⁺=435 (M−H)⁻=433

EXAMPLE 4

[0422]N-(5-aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0423] Prepared analogously to Example 2.b. fromN-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamidein methanolic ammonia/Raney nickel/hydrogen and subsequent reactionanalogously to Example 3.g. with hydrogen in methanol with the additionof palladium on activated charcoal.

[0424] Yield: 34% of theoretical,

[0425] R_(f) value: 0.35 (silica gel; dichloromethane/ethanol=8:2)

[0426] C₂₁H₂₅N₃O₃ (367.45)

[0427] Mass spectrum: (M−H)⁻=366

[0428] The following compounds are prepared analogously to Example 4:

[0429](1)2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-aceticacid-N-ethylamide-hydrochloride

[0430] Yield: 91% of theoretical,

[0431] R_(f) value: 0.13 (silica gel; ethyl acetate/ethanol=3:2+1%ammonia)

[0432] C₂₄H₃₀N₄O₃xHCl (422.53/458.99)

[0433] Mass spectrum: (M+H)⁺=423

[0434] (2)3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-N-ethylamide

[0435] Yield: 28% of theoretical,

[0436] R_(f) value: 0.22 (silica gel; dichloromethane/ethanol=9:1+1%ammonia)

[0437] C₂₅H₃₂N₄O₃ (436.56)

[0438] Mass spectrum: (M+H)⁺=437 (M−H)⁻=435

EXAMPLE 5

[0439]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxycarbonyl-propionyl)amino]-benzamide-hydrochloride

[0440] a. benzyl 4-cyclopentylamino-3-methyl-benzoate

[0441] 3.3 g (13.6 mmol) of benzyl 4-amino-3-methyl-benzoate, 1.3 ml (15mmol) of cyclo-pentanone, 1.2 ml (20.5 mmol) of glacial acetic acid and0.1 g of p-toluenesulphonic acid are dissolved in 70 ml tetrahydrofuranand stirred for 30 minutes at ambient temperature. Then 4.0 g (17.8mmol) of sodium triacetoxyborohydride are added. After 26 hours atambient temperature the solvent is distilled off and the residue isdistributed in water/ethyl acetate. The aqueous phase is extracted threetimes with ethyl acetate. The combined organic extracts are dried andpurified over silica gel, eluting with dichloromethane.

[0442] Yield: 0.8 g (19% of theoretical),

[0443] R_(f) value: 0.78 (silica gel; dichloromethane/ethanol=95:5)

[0444] b. benzyl4-[cyclopentyl-(3-ethoxycarbonyl-propionyl)-amino]-3-methyl-benzoate

[0445] A solution of 0.8 g (2.6 mmol) of benzyl4-cyclopentylamino-3-methyl-benzoate in 30 ml tetrahydrofuran iscombined with 0.1 g (2.6 mmol) of sodium hydride and heated to 40° C.for one hour. After the addition of 0.3 ml (2.34 mmol) of ethylsuccinate chloride the reaction mixture is stirred for 5 days at ambienttemperature. After evaporation of the solvent the residue is taken up inethyl acetate, washed with saline solution and dried. The crude productis purified on silica gel, eluting with dichloromethane.

[0446] Yield: 0.8 g (73% of theoretical),

[0447] R_(f) value: 0.64 (silica gel; dichloromethane/ethanol=95:5)

[0448] c.4-[cyclopentyl-(3-ethoxycarbonyl-propionyl)-amino]-3-methyl-benzoic acid

[0449] Prepared analogously to Example 3.g. from benzyl4-[cyclopentyl-(3-ethoxycarbonyl-propionyl)-amino]-3-methyl-benzoate andpalladium on activated charcoal/hydrogen in methanol.

[0450] Yield: 91% of theoretical,

[0451] R_(f) value: 0.12 (silica gel; dichloromethane/ethanol 95:5)

[0452] d.N-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonyl-propionyl)amino]-benzamide

[0453] Prepared analogously to Example 1.a. from4-[cyclopentyl-(3-ethoxycarbonyl-propionyl)-amino]-3-methyl-benzoicacid, 4-benzyloxy-3-aminomethyl-benzonitrile,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate andN-methylmorpholine in dimethylformamide.

[0454] Yield: 95% of theoretical,

[0455] R_(f) value: 0.28 (silica gel; dichloromethane/ethanol=95:5)

[0456] e.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonyl-propionyl)amino]-benzamide-hydrochloride

[0457] Prepared analogously to Example 1.g. fromN-(5-cyano-2-benzyloxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonylpropionyl)amino]-benzamideand hydrochloric acid/ammonium carbonate in ethanol and subsequentreaction analogously to Example 3.g. with hydrogen in methanol with theaddition of palladium on activated charcoal.

[0458] Yield: 51% of theoretical,

[0459] R_(f) value: 0.31 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 6:4)

[0460] C₂₇H₃₄N₄O₅xHCl (494.60/531.06)

[0461] Mass spectrum: (M+H)⁺=495 (M+Cl)⁻=529/31 (Cl)

[0462] The following compounds are prepared analogously to Example 5:

[0463] (1)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutyl-amino-benzamide-hydrochloride

[0464] Yield: 97% of theoretical,

[0465] R_(f) value: 0.12 (silica gel; dichloromethane/ethanol=4:1)

[0466] C₂₂H₂₆N₄O₃xHCl (394.48/430.94)

[0467] Mass spectrum: (M+H)⁺=395 (M−H)⁻=393 (M+Cl)⁻=429/31 (Cl)

[0468] (2)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methylamino)-benzamide-hydrochloride

[0469] Yield: 91% of theoretical,

[0470] R_(f) value: 0.30 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0471] C₂₂H₂₈N₄O₂xHCl (380.49/416.95)

[0472] Mass spectrum: (M+H)⁺=381 (M−H)⁻=379 (M+Cl)⁻=415/17 (Cl)

EXAMPLE 6

[0473]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionyl)amino]-benzamide-hydrochloride

[0474] 0.2 g (0.28 mmol) ofN-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-(3-ethoxycarbonylpropionyl)amino]-benzamide-hydrochlorideare stirred in 5 ml of 6 molar hydrochloric acid at ambient temperaturefor 4 hours. The solvent is distilled off and the residue is purified onReversed Phase RP 8, eluting with water/methanol (0-50%).

[0475] Yield: 99% of theoretical,

[0476] R_(f) value: 0.49 (Reversed Phase RP 18; 5% sodium chloridesolution/methanol=6:4)

[0477] C₂₅H₃₀N₄O₅xHCl (466.54/503.00)

[0478] Mass spectrum: (M+H)⁺=467 (M−H)⁻=465 (M+Na)⁺=489

EXAMPLE 7

[0479]N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide-hydrochloride

[0480] a. methyl 4-cyclopentylamino-3-methyl-benzoate

[0481] Prepared analogously to Example 1.e. from methyl4-bromo-3-methyl-benzoate, cyclopentylamine, caesium carbonate,palladium-II-acetate and 2,2′-bis-(diphenyl-phosphino)-1,1 ′-binaphthylin toluene.

[0482] Yield: 95% of theoretical,

[0483] R_(f) value: 0.55 (silica gel; dichloromethane)

[0484] b. 4-cyclopentylamino-3-methyl-benzoic acid

[0485] 3.3 g (14 mmol) of methyl 4-cyclopentylamino-3-methyl-benzoateare dissolved in 5 ml methanol and combined with 30 ml of sodiumhydroxide solution (2N). After 12 hours at ambient temperature thereaction mixture is evaporated down and combined with 30 ml hydrochloricacid (2N) with cooling. After 30 minutes the solution is combined withdichloromethane and extracted. The organic phase is dried and evaporateddown.

[0486] Yield: 0.8 g (26% of theoretical),

[0487] R_(f) value: 0.74 (silica gel; petroleum ether/ethyl acetate=4:6)

[0488] c.N-(2-benzyloxy-5-cyano-benzyl)-4-cyclopentylamino-3-methyl-benzamide

[0489] Prepared analogously to Example 1.a. from4-cyclopentylamino-3-methyl-benzoic acid, O-(benzotriazol-1-yl)-N,N,N′-N′-tetramethyluronium fluoroborate, N-methylmorpholine and4-benzyloxy-3-aminomethyl-benzonitrile in dimethylformamide.

[0490] Yield: 49% of theoretical,

[0491] R_(f) value: 0.77 (silica gel; dichloromethane/ethanol 95:5)

[0492] d.N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide-hydrochloride

[0493] Prepared analogously to Example 1.g. fromN-(2-benzyloxy-5-cyano-benzyl)-4-cyclopentylamino-3-methyl-benzamide andhydrochloric acid/ammonium carbonate in ethanol and subsequent reactionwith hydrogen/palladium on activated charcoal in methanol analogously toExample 3.g.

[0494] Yield: 78% of theoretical,

[0495] R_(f) value: 0.29 (silica gel; dichloromethane/ethanol 4:1)

[0496] C₂₁H₂₆N₄O₂xHCl (366.47/402.93)

[0497] Mass spectrum: (M+H)⁺=367 (M−H)⁻=365 (M+Cl)⁻=401/03 (Cl)

EXAMPLE 8

[0498] Ethyl2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-acetate

[0499] a. benzyl tert-butoxycarbonylamino-(3-cyano-phenyl)-acetate

[0500] Prepared analogously to Example 1.c. from benzyltert-butoxycarbonylamino-(3-bromo-phenyl)-acetate andcopper-(I)-cyanide/tetrakis-triphenylphosphine-palladium-(0).

[0501] Yield: 41% of theoretical,

[0502] R_(f) value: 0.25 (silica gel; cyclohexane/ethyl acetate=4:1)

[0503] b. benzyl amino-(3-cyano-phenyl)-acetate

[0504] Prepared analogously to Example 1.d. from benzyltert-butoxycarbonylamino-(3-cyano-phenyl)-acetate and hydrochloric acidin dioxan.

[0505] Yield: 66% of theoretical,

[0506] R_(f) value: 0.4 (silica gel; dichloromethane/methanol95:5+ammonia)

[0507] c. benzyl(3-cyano-phenyl)-{[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonylamino}-acetate

[0508] Prepared analogously to Example 1.a. from benzylamino-(3-cyano-phenyl)-acetate and3-methyl-4-(pyrrolidin-1-carbonyl)-benzoic acid,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate andN-methylmorpholine in dimethylformamide.

[0509] Yield: 93% of theoretical,

[0510] R_(f) value: 0.5 (silica gel; ethyl acetate)

[0511] d. Ethyl(3-carbamimidoyl-phenyl)-{[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-aminol}-acetate

[0512] Prepared analogously to Example 1.g. from benzyl(3-cyano-phenyl)-{[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-amino}-acetate and hydrochloric acid/ammonium carbonate in ethanol.

[0513] Yield: 47% of theoretical,

[0514] R_(f) value: 0.46 (Reversed Phase RP8; 5% salinesolution/methanol=2:3)

[0515] C₂₄H₂₈N₄O₄xCH₃COOH (436.52/496.57)

[0516] Mass spectrum: (M+H)⁺=437 (M−H)⁻=435

EXAMPLE 9

[0517]2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid-hydrochloride

[0518] Prepared analogously to Example 7.b. from ethyl(3-carbamimidoyl-phenyl)-{[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-carbonyl-amino}-acetate and sodium hydroxide solution.

[0519] Yield: 91% of theoretical,

[0520] R_(f) value: 0.55 (Reversed Phase RP8; 5% salinesolution/methanol 2:3)

[0521] C₂₂H₂₄N₄O₄xHCl (408.46/444.92)

[0522] Mass spectrum: (M+H)⁺=409 (M+Na)⁺=431

EXAMPLE 10

[0523]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclopentyl-amino]-benzamide-hydrochloride

[0524] a. methyl4-{cyclopentyl-[2-(2,2,2-trifluoro-acetylamino)-acetyl]-amino}-3-methyl-benzoate

[0525] Prepared analogously to Example 5.b. from methyl4-cyclopentylamino-3-methyl-benzoate,(2,2,2-trifluoro-acetylamino)-acetyl chloride and sodium hydride intetrahydrofuran.

[0526] Yield: 46% of theoretical,

[0527] R_(f) value: 0.65 (silica gel; dichloromethane/ethanol=95:5)

[0528] b.4-[N-(2-benzyloxycarbonylamino-acetyl)-cyclopentyl-amino]-3-methyl-benzoicacid

[0529] 1.5 g (3.8 mmol) of methyl4-{cyclopentyl-[2-(2,2,2-trifluoro-acetyl-amino)-acetyl]-amino}-3-methyl-benzoateare stirred in 20 ml methanol and 7.8 ml (7.7 mmol) of 1 molar sodiumhydroxide solution for 2 hours. The solvent is distilled off, theresidue is combined with 3.9 ml (3.8 mmol) of 1 molar sodium hydroxidesolution. Then 0.6 ml (4.1 mmol) of benzyl chloroformate are addeddropwise. After 1.5 hours the mixture is acidified with 1 molarhydrochloric acid and extracted with ethyl acetate. The combined organicextracts are dried and evaporated down.

[0530] Yield: 1.3 g (80% of theoretical),

[0531] R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=95:5)

[0532] c.N-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-[N-(2-benzyloxycarbonylamino-acetyl)-cyclopentyl-amino]-benzamide

[0533] Prepared analogously to Example 1.a. from4-[N-(2-benzyloxycarbonyl-amino-acetyl)-cyclopentyl-amino]-3-methyl-benzoicacid, 3-aminomethyl-4-benzyloxy-benzonitrile,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborateand N-methylmor-pholine in dimethylformamide.

[0534] Yield: 66% of theoretical,

[0535] R_(f) value: 0.68 (silica gel; dichloromethane/ethanol 95:5)

[0536] d.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-cyclopentyl-amino)]-benzamide-hydrochloride

[0537] Prepared analogously to Example 1.g. fromN-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-[N-(2-benzyloxycarbonylamino-acetyl)-cyclopentyl-amino]-benzamideand hydrochloric acid/ammonium carbonate in ethanol followed by reactionwith hydrogen/palladium on activated charcoal in methanol analogously toExample 3.g.

[0538] Yield: 55% of theoretical,

[0539] R_(f) value: 0.61 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0540] C₂₃H₂₉N₅O₃xHCl (423.52/459.98)

[0541] Mass spectrum: (M+H)⁺=424 (M+Cl)⁻=458/60 (Cl)

[0542] The following compound is prepared analogously to Example 10:

[0543] (1)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(3-amino-propionyl)-N-cylopentyl-amino]-benzamide-hydrochloride

[0544] Yield: 100% of theoretical,

[0545] R_(f) value: 0.53 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0546] C₂₄H₃₁N₅O₃xHCl (437.55/474.01)

[0547] Mass spectrum: (M+H)⁺=438 (M+Cl)⁻=472/74 (Cl)

EXAMPLE 11

[0548]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0549] a. 2-Chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid

[0550] 0.9 g (4.3 mmol) of 2-chloro-terephthalic acid and 0.8 g (4.7mmol) of N,N′-carbonyldiimidazole are stirred in 10 ml dimethylformamidefor 15 minutes. Then 0.5 ml (6.5 mmol) of pyrrolidine and 1.0 ml (9.5mmol) of N-methylmorpholine are added. After 48 hours at ambienttemperature the solvent is distilled off and the residue ischromatographed on silica gel, eluting withdichloromethane/ethanol/glacial acetic acid 95:5:0.02 and 80:20:0.02.

[0551] Yield: 0.3 g (23% of theoretical),

[0552] R_(f) value: 0.21 (silica gel; dichloromethane/ethanol95:5+glacial acetic acid)

[0553] b.N-(2-benzyloxy-5-cyano-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0554] Prepared analogously to Example 1.a. from2-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid,3-aminomethyl-4-benzyloxy-benzonitrile,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate andN-ethyldiisopropylamine in tetrahydro furan.

[0555] Yield: 73% of theoretical,

[0556] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=95:5)

[0557] c.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0558] Prepared analogously to Example 1.g. fromN-(2-benzyloxy-5-cyano-benzyl)-3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzamideand hydrochloric acid/ammonium carbonate in ethanol followed by reactionwith hydrogen/palladium on activated charcoal in methanol analogously toExample 3.g.

[0559] Yield: 66% of theoretical,

[0560] R_(f) value: 0.54 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0561] C₂₀H₂₁CIN₄O₃xHCl (400.87/437.34)

[0562] Mass spectrum: (M+H)⁺=401 (M−H)⁻=399 (M+Cl)⁻=435/7/9 (Cl₂)

EXAMPLE 12

[0563] Ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0564] a. 3-amino-3-(3-cyano-phenyl)-propionic acid

[0565] 13.1 g (0.1 mol) of 3-cyanobenzaldehyde are dissolved in 50 ml of95% ethanol and after the addition of 15.4 g (0.2 mol) of ammoniumacetate stirred for 15 minutes at 45° C. Then 20.8 g (0.2 mol) ofmalonic acid in 50 ml of 95% ethanol are added dropwise. The reactionmixture is refluxed for 2 hours. The crystalline product is suctionfiltered and recrystallised from methanol/water.

[0566] Yield: 6.5 g (34% of theoretical),

[0567] C₁₀H₁₀N₂O₂ (190.20)

[0568] Mass spectrum: (M+H)⁺=191 (M−H)⁻=189

[0569] b.3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid

[0570] 380.4 mg (2 mmol) of 3-amino-3-(3-cyano-phenyl)-propionic acidare added to 2.0 ml of 2 molar sodium hydroxide solution while coolingwith ice. After the addition of 500 mg (1.98 mmol) of3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylchloride the reactionmixture is stirred for 4 hours at ambient temperature. The solution isdiluted with water and adjusted to pH 4 with 1 M hydrochloric acid. Theprecipitate formed is suction filtered and chromatographed on silicagel, eluting with dichloromethane/ethanol (4-10%).

[0571] Yield: 280 mg (35% of theoretical),

[0572] R_(f) value: 0.35 (silica gel; dichloromethane/ethanol=9:1)

[0573] c. Ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionatehydrochloride

[0574] Prepared analogously to Example 1.g. from3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid and hydrochloric acid/ammonium carbonate in ethanol.

[0575] Yield: 59% of theoretical,

[0576] R_(f) value: 0.40 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0577] C₂₅H₃₀N₄O₄xHCl (450.54/487.01)

[0578] Mass spectrum: (M+H)⁺=451 (M−H)⁻=449 (M+Cl)⁻=585/87 (Cl)

[0579] The following compounds are prepared analogously to Example 12:

[0580] (1) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0581] Yield: 98% of theoretical,

[0582] R_(f) value: 0.22 (silica gel; dichloromethane/ethanol=4:1)

[0583] C₂₄H₂₇CIN₄O₄xHCl (470.69/507.43)

[0584] Mass spectrum: (M+H)⁺=471/73 (Cl) (M+Cl)⁻=505/7/9 (Cl₂)

[0585] (2) ethyl3-(3-carbamimidoyl-phenyl)-3-{3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzoylamino}-propionate-hydrochloride

[0586] Yield: 100% of theoretical,

[0587] R_(f) value: 0.28 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0588] C₂₈H₃₇N₅O₄xHCl (507.63/544.11)

[0589] Mass spectrum: (M+H)⁺=508 (M+Cl)⁻=542/44 (Cl)

[0590] (3) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl-benzoylamino]-propionate-hydrochloride

[0591] Yield: 81% of theoretical,

[0592] R_(f) value: 0.70 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 1:4)

[0593] C₂₄H₂₇BrN₄O₄xHCl (515.41/551.87)

[0594] Mass spectrum: (M+H)⁺=515/17 (Br)

[0595] (4) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0596] Yield: 45% of theoretical,

[0597] R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=4:1+1%glacial acetic acid)

[0598] C₂₅H₂₈N₄O₄xHCl (448.51/484.91)

[0599] Mass spectrum: (M+H)⁺=449 (M+Cl⁻)⁻=483/5 (Cl)

[0600] (5) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate-hydrochloride

[0601] Yield: 71% of theoretical,

[0602] R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=3:1)

[0603] C₂₆H₂₈N₄O₄xHCl (460.53/497.01)

[0604] Mass spectrum: (M+H)⁺=461 (M+Cl⁻)⁻=495/7 (Cl)

[0605] (6) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0606] Yield: 38% of theoretical,

[0607] R_(f) value: 0.18 (silica gel; dichloromethane/ethanol=4:1)

[0608] C₂₆H₃₂N₄O₄xHCl (464.56/501.03)

[0609] Mass spectrum: (M+H)⁺=465 (M+Cl⁻)⁻=499/501 (Cl)

[0610] (7) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate-hydrochloride

[0611] Yield:

[0612] R_(f) value:

[0613] C₂₆H₃₀N₄O₄xHCl (462.55/499.0)

[0614] Mass spectrum:

EXAMPLE 13

[0615]3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0616] Prepared analogously to Example 6 from ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochlorideand 6 molar hydrochloric acid.

[0617] Yield: 85% of theoretical,

[0618] R_(f) value: 0.50 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0619] C₂₃H₂₆N₄O₄xHCl (422.49/458.96)

[0620] Mass spectrum: (M+H)⁺=423 (M−H)⁻=421

[0621] The following compounds are obtained analogously to Example 13:

[0622] (1)3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0623] Yield: 65% of theoretical,

[0624] R_(f) value: 0.5 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0625] C₂₃H₂₃F₃N₄O₄xHCl (476.46/512,91)

[0626] Mass spectrum: (M+H)⁺=477 (M−H)⁻=475

[0627] (2)3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0628] Yield: 90% of theoretical,

[0629] R_(f) value: 0.42 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0630] C₂₂H₂₃CIN₄O₄xHCl (442.9/479.38)

[0631] Mass spectrum: (M+H)⁺=443/5 (Cl) (M−H)⁻=441/3 (Cl)

[0632] (3)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2.5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0633] Yield: 27% of theoretical,

[0634] R_(f) value: 0.40 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0635] C₂₃H₂₄N₄O₄xHCl (420.46/456.93)

[0636] Mass spectrum: (M+H)⁺=421 (M−H)⁻=419

[0637] (4)3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0638] Yield: 86% of theoretical,

[0639] R_(f) value: 0.15 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0640] C₂₄H₂₄N₄O₄xHCl (432.88/468.95)

[0641] Mass spectrum: (M+H)⁺=433 (M−H)⁻=431 (M+Cl)⁻=467/9

[0642] (5)3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0643] Yield: 85% of theoretical,

[0644] R_(f) value: 0.57 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0645] C₂₄H₂₈N₄O₄xHCl (436.51/472.98)

[0646] Mass spectrum: (M+H)⁺=437 (M−H)⁻=435 (M+Cl)⁻=471/3

[0647] (6)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-methyl-N-(hydroxycarbonylmethyl)-amide-hydrochloride

[0648] Yield: 42% of theoretical,

[0649] R_(f) value: 0.35 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0650] C₂₆H₃₁N₅O₅xHCl (493.56/530.03)

[0651] Mass spectrum: (M+H)⁺=494 (M−H)⁻=492 (M+Cl)⁻=528/30

[0652] (7)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(hydroxycarbonylmethyl)-N-(n-propyl)-amide-hydrochloride

[0653] Yield: 67% of theoretical,

[0654] R_(f) value: 0.33 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0655] C₂₈H₃₅N₅O₅xHCl (521.62/558.08)

[0656] Mass spectrum: (M+H)⁺=522 (M−H)⁻=520

[0657] (8)3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid-hydrochloride

[0658] Yield:

[0659] R_(f) value:

[0660] C₂₄H₂₆N₄O₄xHCl (434.50/470.95)

[0661] Mass spectrum:

EXAMPLE 14

[0662]3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-N,N-dimethylamide-hydrochloride

[0663] a.3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid dimethylamide

[0664] Prepared analogously to Example 1.a. from3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, dimethylamine, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumtetrafluoroborate and N-methylmorpholine in dimethylformamide.

[0665] Yield: 36% of theoretical,

[0666] R_(f) value: 0.38 (silica gel; dichloromethane/ethanol=19:1)

[0667] b.3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid dimethylamide-hydrochloride

[0668] Prepared analogously to Example 1.g. from3-(3-cyano-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-dimethylamide and hydrochloric acid/ammonium carbonate in ethanol.

[0669] Yield: 24% of theoretical,

[0670] R_(f) value: 0.17 (silica gel; dichloromethane/ethanol 4:1+1%glacial acetic acid)

[0671] C₂₅H₃₁N₅O₃xHCl (449.56/486.03)

[0672] Mass spectrum: (M+H)⁺=450 (M+Cl)⁻=484/86 (Cl)

[0673] The following are prepared analogously to Example 14:

[0674] (1)N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0675] Yield: 79% of theoretical

[0676] R_(f) value: 0.40 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0677] C₂₆H₃₁N₅O₃xHCl (461.53/498.03)

[0678] Mass spectrum: (M+H)⁺=462

[0679] (2)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-aceticacid-N,N-dimethylamide-hydrochloride

[0680] Yield: 76% of theoretical

[0681] R_(f) value: 0.46 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0682] C₂₄H₂₉N₅O₃xHCl (435.53/471.99)

[0683] Mass spectrum: (M+H)⁺=436

[0684] (3)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-aceticacid-N-ethylamide-hydrochloride

[0685] Yield: 56% of theoretical

[0686] R_(f) value: 0.38 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0687] C₂₄H₂₉N₅O₃xHCl (435.53/471.99)

[0688] Mass spectrum: (M+H)⁺=436

[0689] (4)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-N-ethylamide-hydrochloride

[0690] Yield: 43% of theoretical

[0691] R_(f) value: 0.25 (silica gel; dichloromethane/ethanol=4:1+1%glacial acetic acid)

[0692] C₂₅H₃₁N₅O₃xHCl (449.55/486.02)

[0693] Mass spectrum: (M+H)⁺=450 (M−H)⁻=448 (M+Cl)⁻=484/6 (Cl)

[0694] (5)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(ethoxycarbonylmethyl)-N-(n-propyl)-amide-hydrochloride

[0695] Yield: 91% of theoretical

[0696] R_(f) value: 0.27 (silica gel; dichloromethane/ethanol=4:1+1%glacial acetic acid)

[0697] C₃₀H₃₉N₅O₃xHCl (549.67/586.14)

[0698] Mass spectrum: (M+H)⁺=550 (M+Cl)⁻=584/6 (Cl)

EXAMPLE 15

[0699]N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0700] a. 3-(1-amino-ethyl)-4-benzyloxy-benzonitrile

[0701] 10.4 g (41.4 mmol) of 3-acetyl-4-benzoyl-benzonitrile aredissolved in 40 ml methanol, combined with 31.0 g (0.4 mol) of ammoniumacetate and, after the addition of 1.8 g (28 mmol) of sodiumcyanoborohydride, refluxed for 3 days under a nitrogen atmosphere. Thesolvent is distilled off, the residue is stirred in semiconc.hydrochloric acid for 30 minutes, neutralised with ammonia and extractedwith ethyl acetate. The combined organic extracts are evaporated downand chromatographed on silica gel, eluting with petroleum ether/ethanol9:1 and with ethyl acetate/ethanol 7:3.

[0702] Yield: 1.3 g (12% of theoretical),

[0703] R_(f) value: 0.15 (silica gel; ethyl acetate/ethanol=9:1)

[0704] b.N-[1-(2-benzyloxy-5-cyano-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0705] Prepared analogously to Example 1.a. from3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid,3-(1-amino-ethyl)-4-benzyloxy-benzonitrile,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborateand N-methylmorpholine in dimethylformamide.

[0706] Yield: 63% of theoretical,

[0707] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=19:1)

[0708] c.N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0709] Prepared analogously to Example 1.g. fromN-[1-(2-benzyloxy-5-cyano-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamideand hydrochloric acid/ammonium carbonate in ethanol followed by reactionwith hydrogen/palladium on activated charcoal in methanol analogously toExample 3.g.

[0710] Yield: 30% of theoretical,

[0711] R_(f) value: 0.35 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0712] C₂₂H₂₆N₄O₃xHCl (394.48/430.95)

[0713] Mass spectrum: (M+H)⁺=395 (M−H)⁻=393 (M+Cl)⁻=429/31 (C1)

[0714] The following compounds are prepared analogously to Example 15:

[0715] (1)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0716] Yield: 3% of theoretical

[0717] R_(f) value: 0.50 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0718] C₂₁H₂₃BrN₄O₃xHCl (459.35/495.82)

[0719] Mass spectrum: (M+H)⁺=459/61 (Br)

[0720] (2)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0721] Yield: 5% of theoretical

[0722] R_(f) value: 0.58 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3) C₂₁H₂₄N₄O₃xHCl (380.45/416.92)

[0723] Mass spectrum: (M+H)⁺=381

EXAMPLE 16

[0724] Ethyl3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0725] a. 4-methyl-3-trifluoromethyl-benzonitrile

[0726] 10.0 g (57 mmol) of 4-methyl-3-trifluoromethyl-aniline aresuspended in 50 ml of semiconcentrated hydrochloric acid and at 0° C.combined with a solution of 4.2 g (61 mmol) of sodium nitrite in 25 mlof water. The diazonium salt solution formed is then added dropwise at30° C. to a solution of 12.5 g (0.14 mol) of copper-(I)-cyanide and 25 g(0.38 mol) of potassium cyanide in 160 ml of water. The suspensionformed is heated to 78° C. for 2 hours. After cooling the undissolvedmaterial is filtered off, the filtrate is combined with 250 ml ethylacetate and extracted. The combined organic phases are washed untilneutral, dried and evaporated down. The crude product is purified bysublimation at 40-90° C. and 12 mbar.

[0727] Yield: 5.5 g (47% of theoretical),

[0728] R_(f) value: 0.43 (silica gel; cyclohexane/ethyl acetate=4:1)

[0729] b. 4-cyano-2-trifluoromethyl-benzoicacid/4-aminocarbonyl-2-trifluoromethyl-benzoic acid

[0730] 28 ml of conc. sulphuric acid are added dropwise at ambienttemperature to a suspension of 4.5 g (24.3 mmol) of4-methyl-3-trifluoromethyl-benzonitrile and 11 g (37.4 mmol) ofpotassium dichromate in 100 ml glacial acetic acid, while thetemperature rises to 80° C. After 1.5 hours at 115° C. the reactionmixture is cooled, poured onto a mixture of 300g of ice/300 ml ofsaturated saline solution, adjusted to pH 3.5 with conc. ammonia andextracted with a total of 1000 ml of ethyl acetate. The combined organicphases are evaporated down by half, adjusted to pH 9 with conc. ammoniaand extracted with a total of 400 ml of 0.1 N sodium hydroxide solution.The aqueous phase is adjusted to pH 3.5 by the addition of conc.hydrochloric acid and extracted with a total of 400 ml of ethyl acetate.The combined organic extracts are washed with saturated saline solution,dried and evaporated down.

[0731] Yield: 2.6 g (product mixture in a ratio of 3:7, 47% oftheoretical),

[0732] R_(f) values:

[0733] 4-cyano-2-trifluoromethyl-benzoic acid: 0.3 (silica gel;methylene chloride/ethanol=6.5 3.5+glacial acetic acid)

[0734] 4-aminocarbonyl-2-trifluoromethyl-benzoic acid: 0.2 (silica gel;methylene chloride/ethanol=6.5:3.5+glacial acetic acid)

[0735] c.3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile/3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0736] Prepared analogously to Example 1.a. from4-cyano-2-trifluoromethyl-benzoicacid/4-aminocarbonyl-2-trifluoromethyl-benzoic acid, pyrrolidine,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate andN-methylmorpholine in dimethylformamide.

[0737] Yield: 53% of theoretical (product mixture),

[0738] R_(f) values:

[0739] 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile: 0.35(silica gel; ethyl acetate/ethanol=85:15+glacial acetic acid)

[0740] 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide: 0.35(silica gel; ethyl acetate/ethanol=85:15+glacial acetic acid)

[0741] d. 3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid

[0742] 1.65 g of a mixture of3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzonitrile and3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide are dissolvedin 20 ml ethanol and combined with 20 ml of 10 N sodium hydroxidesolution. After 45 minutes at 80° C. the reaction solution is pouredonto ice water and adjusted to pH 9 with conc. hydrochloric acid. Theethanol is distilled off and the residue is extracted with 100 ml etherand 50 ml ethyl acetate. The aqueous phase is adjusted to pH 3.5 withconc. hydrochloric acid, the white precipitate formed is suctionfiltered and dried.

[0743] Yield: 1.05 g (85% of theoretical),

[0744] R_(f) value: 0.43 (silica gel; ethylacetate/ethanol=85:15+glacial acetic acid)

[0745] e. ethyl3-(3-cyano-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate

[0746] Prepared analogously to Example 1.a. from3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,N-methylmorpholine and ethyl 3-amino-3-(3-cyano-phenyl)-propionate indimethylformamide.

[0747] Yield: 64% of theoretical,

[0748] R_(f) value: 0.7 (silica gel; ethyl acetate/ethanol=9:1)

[0749] f. ethyl3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0750] Prepared analogously to Example 1.g. from ethyl3-(3-cyano-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionateand hydrochloric acid/ammonium carbonate in ethanol.

[0751] Yield: 90% of theoretical,

[0752] R_(f) value: (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0753] C₂₅H₂₇F₃N₄O₄xHCl (504.51/540.97)

[0754] Mass spectrum: (M+H)⁺=505

EXAMPLE 17

[0755]N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0756] a. 3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzoic acid

[0757] 1.8 g of carbonyldiimidazole (15.6 mmol) and 2.5 ml ofN-methylmorpholine (22.7 mmol) are added to a solution of 2.5 g of2-(trifluoromethoxy)-terephthalic acid (19 mmol) in 40 ml ofdimethylformamide at ambient temperature. After 10 minutes 1.3 ml ofpyrrolidine (15.6 mmol) are added dropwise. The reaction mixture isstirred for 3 days at ambient temperature, then stirred into ice water,adjusted to pH 4 with 1 N hydrochloric acid and extracted 3× with 100 mlof ethyl acetate. The combined organic phases are washed with salinesolution, dried and evaporated down. The crude product is purified onsilica gel, eluting initially with dichloromethane, then withdichloromethane/ethanol 50:1, 25:1, 19:1 and 9:1. The uniform fractionsare combined and evaporated down.

[0758] Yield: 90 mg (3% of theoretical),

[0759] R_(f) value: 0.27 (silica gel; dichloromethane/ethanol=9:1)

[0760] b.N-(2-benzyloxy-5-cyano-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0761] Prepared analogously to Example 1.a. from3-trifluoromethyl-4-(pyrrolidin-1-carbonyl)-benzoic acid,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,N-methylmorpholine and 4-benzyloxy-3-aminomethyl-benzonitrile indimethylformamide.

[0762] Yield: 62% of theoretical,

[0763] R_(f) value: 0.5 (silica gel; dichloromethane/ethanol=9:1)

[0764] c.N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0765] Prepared analogously to Example 1.g. fromN-(2-benzyloxy-5-cyano-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamideand hydrochloric acid/ammonium carbonate in ethanol followed by reactionwith hydrogen/palladium on activated charcoal in methanol analogously toExample 3.g.

[0766] Yield: 24% of theoretical,

[0767] R_(f) value: 0.3 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0768] C₂₁H₂₁F₃N₄O₄xHCl (450.42/486.88)

[0769] Mass spectrum: (M+H)⁺=451 (M−H)⁻=449

EXAMPLE 18

[0770]3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0771] a. 4-amino-2-oxo-chroman-6-carbonitrile-hydrochloride

[0772] 4.6 ml of a 1 N solution of bis-(trimethylsilyl)-lithium amide intetrahydrofuran (4.6 mmol) are added dropwise to a solution of 750 mg of2-oxo-2H-chromene-6-carbonitrile (4.4 mmol) at −70° C. After 5 minutesat −70° C. and 2 hours at −15° C. the reaction mixture is poured onto180 ml of diethylether and combined with ethereal hydrochloric acid. Theprecipitate formed is filtered off, dried and further reacted withoutpurification.

[0773] Yield: 1.0 g (56% of theoretical),

[0774] R_(f) value: 0.45 (silica gel; ethyl acetate/ethanol=9:1+1%ammonia))

[0775] b.3-(5-cyano-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid

[0776] Prepared analogously to Example 12.b. from4-amino-2-oxo-chromane-6-carbonitrile-hydrochloride,3-methyl-4-(pyrrolidin-1-carbonyl)-benzoylchloride and triethylamine intetrahydrofuran.

[0777] Yield: 39% of theoretical,

[0778] R_(f) value: 0.5 (silica gel; ethyl acetate/ethanol=4:1+1%glacial acetic acid)

[0779] c. ethyl3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate-hydrochloride

[0780] Prepared analogously to Example 1.g. from3-(5-cyano-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid and hydrochloric acid/ammonium carbonate in ethanol.

[0781] Yield: 69% of theoretical,

[0782] R_(f) value: 0.5 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0783] d.3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-hydrochloride

[0784] Prepared analogously to Example 11. from ethyl3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionatehydrochloride and 6 N hydrochloric acid.

[0785] Yield: 43% of theoretical,

[0786] R_(f) value: 0.6 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol 2:3)

[0787] C₂₃H₂₆N₄O₅xHCl (438.48/474.95)

[0788] Mass spectrum: (M+H)⁺=439

EXAMPLE 19

[0789] Ethyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate

[0790] A suspension of 390 mg (0.8 mmol) of ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionateand 1.0 ml triethylamine in 40 ml dichloromethane is combined with 275mg (1.1 mmol) of 4-nitrophenyl benzoate and refluxed for 7 hours. Thesolvent is evaporated off, the residue is taken up in ice water andadjusted to pH 4 with 1N hydrochloric acid. After extraction with ethylacetate the combined organic phases are washed with saline solution anddried. The crude product is purified on silica gel, eluting initiallywith dichloromethane, then with dichloromethane/ethanol 50:1 and 25:1.

[0791] Yield: 55 mg (12% of theoretical),

[0792] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=19:1)

[0793] C₃₂H₃₄N₄O₅ (554.65)

[0794] Mass spectrum: (M+H)⁺=555 (M−H)⁻=553

[0795] The following compounds are prepared analogously to Example 19:

[0796] (1) ethyl3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate

[0797] Yield: 47% of theoretical,

[0798] R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=19:1+1%ammonia)

[0799] C₃₂H₄₂N₄O₆xHCl (578.71/615.18)

[0800] Mass spectrum: (M+H)⁺=579

[0801] (2) n-propyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate

[0802] Yield: 23% of theoretical,

[0803] R_(f) value: 0.70 (silica gel; ethyl acetate/ethanol=9:1)

[0804] C₃₃H₃₆N₄O₅ (568.68)

[0805] Mass spectrum: (M+H)⁺=569 (M−H)⁻=567

[0806] (3) ethyl3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate

[0807] Yield: 45% of theoretical,

[0808] R_(f) value: 0.70 (silica gel; ethyl acetate/ethanol=9:1)

[0809] C₂₈H₃₁Cl₃N₄O₆ (625.94)

[0810] Mass spectrum: (M+H)⁺=625/7/9 (Cl₃) (M−H)⁻=623/5/7 (Cl₃)(M+HCOO)⁻=669/71/71 (Cl₃)

[0811] (4)N-{5-[N-(n-hexyloxycarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0812] Yield: 11% of theoretical,

[0813] R_(f) value: 0.50 (silica gel; ethyl acetate/ethanol=9:1)

[0814] C₂₈H₃₆N₄O₅ (508.62)

[0815] Mass spectrum: (M+H)⁺=509 (M−H)⁻=507

[0816] (5) N—{5-[N-(phenylcarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0817] Yield: 46% of theoretical,

[0818] R_(f) value: 0.45 (silica gel; ethyl acetate/ethanol 9:1)

[0819] C₂₈H₂₈N₄O₄ (484.56)

[0820] Mass spectrum: (M+H)⁺=585 (M−H)⁻=583

EXAMPLE 20

[0821]N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0822] a.N-(5-N-hydroxyamidino-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0823] A solution of 482 mg (1.06 mmol) ofN-(2-benzyloxy-5-cyano-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamidein 20 ml methanol/ethanol (1:1) is combined with a solution of 148 mg(2.1 mmol) of hydroxylamine hydrochloride and 174 mg (2.1 mmol) ofsodium acetate in 1.0 ml of water and refluxed for 7 hours. Aftercooling the reaction mixture is combined with ice water and extractedwith ethyl acetate. The combined organic phases are washed with salinesolution, dried and evaporated down. The crude product is purified onsilica gel, eluting initially with dichloromethane, then withdichloromethane/ethanol 25:1, 19:1 and 9:1.

[0824] Yield: 210 mg (41% of theoretical),

[0825] R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=19:1)

[0826] b.N-(5-N-hydroxyamidino-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide-hydrochloride

[0827] Prepared analogously to Example 3.g. fromN-(5-N-hydroxyamidino-2-benzyloxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamideand hydrogen/palladium on activated charcoal.

[0828] Yield: 41% of theoretical,

[0829] R_(f) value: 0.3 (Reversed Phase RP 8; 5% sodium chloridesolution/methanol=2:3)

[0830] C₂₁H₂₄N₄O₄xHCl (396.45/432.91)

[0831] Mass spectrum: (M+H)⁺=397 (M−H)⁻=395

EXAMPLE 21

[0832]N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide

[0833] 121 mg (0.25 mmol) ofN-(5-phenylcarbonylamidino-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamideare dissolved in 10 ml isopropanol with heating and combined with asolution of 41.5 mg (0.3 mmol) of potassium carbonate in 0.5 ml ofwater. After 10 minutes a solution of 32.6 mg (0.3 mmol) of ethylchloroformate in 1 ml of isopropanol is added. After 1 hour at ambienttemperature the reaction solution is stirred into ice water. Theprecipitate formed is suction filtered, washed with water and dried.

[0834] Yield: 72 mg (52% of theoretical),

[0835] R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

[0836] C₃₁H₃₂N₄O₆ (556.62)

[0837] Mass spectrum: (M+H)⁺=557 (M−H)⁻=555

EXAMPLE 22

[0838] Dry ampoule containing 75 mg of active substance per 10 ml

[0839] Composition: Active substance 75.0 mg Mannitol 50.0 mg water forinjections ad 10.0 ml

[0840] Preparation:

[0841] Active substance and mannitol are dissolved in water. Afterpackaging the solution is freeze-dried. To produce the solution readyfor use, the product is dissolved in water for injections.

EXAMPLE 23

[0842] Dry ampoule containing 35 mg of active substance per 2 ml

[0843] Composition: Active substance 35.0 mg Mannitol 100.0 mg water forinjections ad 2.0 ml

[0844] Preparation:

[0845] Active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried.

[0846] To produce the solution ready for use, the product is dissolvedin water for injections.

EXAMPLE 24

[0847] Tablet containing 50 mg of active substance

[0848] Composition: (1) Active substance 50.0 mg (2) Lactos 98.0 mg (3)Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesiumstearate 2.0 mg 215.0 mg

[0849] Preparation:

[0850] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0851] Diameter of the tablets: 9 mm.

EXAMPLE 25

[0852] Tablet containing 350 mg of active substance

[0853] Composition: (1) Active substance 350.0 mg (2) Lactose 136.0 mg(3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesiumstearate 4.0 mg 600.0 mg

[0854] Preparation:

[0855] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side. Diameter of the tablets: 12 mm.

EXAMPLE 26

[0856] Capsules containing 50 mg of active substance

[0857] Composition: (1) Active substance 50.0 mg (2) Dried maize starch58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0mg

[0858] Preparation:

[0859] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0860] This powder mixture is packed into size 3 hard gelatine capsulesin a capsule filling machine.

EXAMPLE 27

[0861] Capsules containing 350 mg of active substance

[0862] Composition: (1) Active substance 350.0 mg (2) Dried maize starch46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0mg

[0863] Preparation:

[0864] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0865] This powder mixture is packed into size 0 hard gelatine capsulesin a capsule filling machine.

EXAMPLE 28

[0866] Suppositories containing 100 mg of active substance 1 suppositorycontains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitanmonostearate 840.0 mg 2,000.0 mg

[0867] Preparation:

[0868] The polyethyleneglycol is melted together withpolyethylenesorbitan monostearate. At 40° C. the ground active substanceis homogeneously dispersed in the melt. This is then cooled to 38° C.and poured into slightly chilled suppository moulds.

What is claimed is:
 1. A compound of the formula

wherein: (i) m denotes the number 0, n denotes the number 1 and Adenotes a straight-chain C₁₋₃-alkylene group wherein one or two hydrogenatoms independently of one another may be replaced in each case by aC₁₋₃-alkyl group or a hydrogen atom may be replaced by the group—(CH₂)_(p)—R_(f), while p denotes one of the numbers 0, 1, 2 or 3 andR_(f) denotes a hydroxycarbonyl, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,C₃₋₇-cycloalkylamino-carbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group, or (ii) m denotes the number 1, ndenotes the number 1 and A denotes a bond or (iii) m denotes the number0 or 1, n denotes the number 0 and A denotes a straight-chainC₁₋₃-alkylene group wherein one or two hydrogen atoms independently ofone another may be replaced in each case by a C₁₋₃-alkyl group, or (iv)m denotes the number 2, n denotes the number 0 and A denotes a bond, R₁denotes an amino, C₁₋₅-alkylamino, C₃₋₇-cycloalkylamino orphenyl-C₁₋₃-alkylamino group each of which may be substituted at theamino nitrogen atom by a phenylcarbonyl or phenylsulphonyl group or by aC₁₋₃-alkyl or C₁₋₃-alkyl-carbonyl group optionally substituted in thealkyl moiety by a carboxy group, a group which may be converted in vivointo a carboxy group, an amino, C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)-aminogroup, a di-(C₁₋₅-alkyl)amino or N-(C₃₋₇-cycloalkyl)-C₁₋₅-alkylaminogroup, while the C₁₋₅-alkyl moiety with the exception of the 1 positionmay be substituted in each case by a hydroxy, C₁₋₃-alkoxy, amino,C₁₋₃-alkyl-amino or di-(C₁₋₃-alkyl)-amino group, a 4- to 7-memberedcycloalkyleneiminocarbonyl or cycloalkyleneiminosulphonyl groupoptionally substituted by a C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,aminocarbonyl, C₁₋₃-alkylamino-carbonyl or di-(C₁₋₃-alkyl)-aminocarbonylgroup, a 2,5-dihydropyrrol-1-yl-carbonyl group, an aminosulphonyl groupoptionally substituted by one or two C₁₋₃-alkyl groups, aC₃₋₇-cycloalkyl-carbonyl group, whilst the methylene group in the 3 or 4position in a C₅₋₇-cycloalkyl-carbonyl group may be replaced by an —NHgroup wherein the hydrogen atom of the —NH group may be replaced by aC₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, phenylcarbonyl or phenylsulphonylgroup, a phenylcarbonyl or heteroarylcarbonyl group, or a C₁₋₃-alkylgroup optionally monosubstituted by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, hydroxy, phenyl or a 4- to 7-memberedcycloalkyleneimino group or terminally disubstituted by a phenyl groupand a hydroxy group, while the phenyl substituents may be substituted byan amidino group optionally substituted by one or two C₁₋₃-alkyl groups,by a fluorine, chlorine or bromine atom, by a trifluoromethyl,C₁₋₃-alkyl or C₁₋₃-alkoxy group, R₂ denotes a hydrogen, fluorine,chlorine or bromine atom, a C₁₋₃-alkyl group wherein the hydrogen atomsmay be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl,C₂₋₃-alkynyl, hydroxy, C₁₋₃-alkoxy or trifluoromethoxy group, R₃ denotesa hydrogen atom or a C₁₋₃-alkyl group, R₄ denotes a hydrogen atom or aC₁₋₃-alkyl group optionally substituted by a carboxy group or a groupwhich may be converted in vivo into a carboxy group and Ar denotes aphenyl or naphthyl group substituted by the groups R₅, R₆ and R₇, whileR₅ denotes a cyano group, an amidino group optionally substituted by oneor two C₁₋₃-alkyl groups, an amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl or di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyl group, R₆denotes a hydrogen, fluorine, chlorine or bromine atom, atrifluoromethyl, C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy,C₁₋₃-alkoxy-C₁₋₃-alkyl, carboxy, carboxy-C₁₋₃-alkyl,carboxy-C₁₋₃-alkoxy, C₁₋₄-alkoxy-carbonyloxy,C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, phenyl-C₁₋₃-alkoxy, amino,C₁₋₃-alkylamino or di-(C₁₋₃-alkyl)amino group and R₇ denotes a hydrogen,fluorine, chlorine or bromine atom or a C₁₋₃-alkyl group, or a thienyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl groupoptionally substituted in the carbon skeleton by a C₁₋₃-alkyl group,while the term heteroaryl group mentioned above denotes a 5-memberedheteroaryl group bound via a carbon or nitrogen atom which contains animino group optionally substituted by a C₁₋₄-alkyl orC₁₋₄-alkyl-carbonyl group, an oxygen or sulphur atom, an imino groupoptionally substituted by a C₁₋₄-alkyl group or an oxygen or sulphuratom and additionally a nitrogen atom, an imino group optionallysubstituted by a C₁₋₄-alkyl group and two nitrogen atoms or an oxygen orsulphur atom and two nitrogen atoms, or a 6-membered heteroaryl groupwhich contains one or two nitrogen atoms, while a phenyl ring may befused to the abovementioned 5- or 6-membered heteroaryl groups via twoadjacent carbon atoms and the bicyclic heteroaryl groups thus formed maybe bound via the heteroaromatic or carbocyclic moiety, and theunsubstituted or monosubstituted phenyl groups mentioned in thedefinition of the abovementioned groups, or the unsubstituted ormonosubstituted phenyl moieties contained in these groups, as well asthe abovementioned heteroaryl groups may additionally be substituted ata carbon atom in each case by a fluorine, chlorine or bromine atom, by atrifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group, unless otherwisestated, the carboxy groups mentioned in the definition of theabovementioned groups may be replaced by a group which may be convertedin vivo into a carboxy group or by a group which is negatively chargedunder physiological conditions, and the amino and imino groups mentionedin the definition of the abovementioned groups may be substituted by agroup which can be cleaved in vivo, or a salt thereof.
 2. A compound ofthe formula I according to claim 1, wherein: (i) m denotes the number 0,n denotes the number 1 and A denotes a straight-chain C₁₋₃-alkylenegroup wherein one or two hydrogen atoms independently of one another maybe replaced in each case by a C₁₋₃-alkyl group or a hydrogen atom may bereplaced by the group —(CH₂)_(p)—R_(f), while p denotes one of thenumbers 0, 1, 2 or 3 and R_(f) denotes a hydroxycarbonyl,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₇-cycloalkylamino-carbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group, or (ii) m denotes the number 0 or 1,n denotes the number 0 and A denotes a straight-chain C₁₋₃-alkylenegroup wherein one or two hydrogen atoms independently of one another maybe replaced in each case by a C₁₋₃-alkyl group, R₁ denotes an amino,C₁₋₃-alkylamino or C₃₋₇-cycloalkylamino group each of which may besubstituted at the amino nitrogen atom by a C₁₋₃-alkyl,C₁₋₃-alkylcarbonyl, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₃-alkylcarbonyl,C₁₋₆-alkoxy-carbonyl-C₁₋₃-alkyl-carbonyl or amino-C₁₋₃-alkyl-carbonylgroup, a di-(C₁₋₃-alkyl)amino or N-(C₅₋₇-cycloalkyl)-C₁₋₃-alkylaminogroup, a 4- to 7-membered cycloalkyleneiminocarbonyl group optionallysubstituted by a C₁₋₃-alkyl, amino-C₁₋₃-alkyl,C₁₋₃-alkylamino-C₁₋₃-alkyl, aminocarbonyl or C₁₋₃-alkylamino-carbonylgroup, while a hydrogen atom bound to a nitrogen atom may be replaced byan acetyl, phenylcarbonyl or tert.-butoxycarbonyl group, or a2,5-dihydropyrrol-1-yl-carbonyl group, R₂ denotes a hydrogen, fluorine,chlorine or bromine atom, a C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkynyl,trifluoromethyl, C₁₋₃-alkoxy or trifluoromethoxy group, R₃ denotes ahydrogen atom or a C₁₋₃-alkyl group, R₄ denotes a hydrogen atom or aC₁₋₃-alkyl group and Ar denotes a phenyl group substituted by the groupsR₅, R₆ and R₇, while R₅ denotes a cyano group, an amidino groupoptionally substituted by one or two C₁₋₃-alkyl groups, a hydroxy,C₁₋₆-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonylgroup, or an amino-C₁₋₃-alkyl or C₁₋₃-alkylamino-C₁₋₃-alkyl group, R₆denotes a hydrogen, fluorine, chlorine or bromine atom, atrifluoromethyl, C₁₋₃-alkyl, hydroxy, hydroxy-C₁₋₃-alkyl, C₁₋₃-alkoxy,carboxy, C₁₋₃-alkoxy-carbonyloxy, carboxy-C₁₋₃-alkoxy orC₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy group and R₇ denotes a hydrogen atom ora C₁₋₃-alkyl group, while the unsubstituted or monosubstituted phenylgroups mentioned in the definition of the abovementioned groups, or theunsubstituted or monosubstituted phenyl moieties contained in thesegroups, as well as the abovementioned heteroaryl groups may additionallybe substituted at a carbon atom in each case by a fluorine, chlorine orbromine atom, by a trifluoromethyl, C₁₋₃-alkyl or C₁₋₃-alkoxy group,unless otherwise stated, or a salt thereof.
 3. A compound of the formulaI according to claim 2, wherein: (i) m denotes the number 0, n denotesthe number 1 and A denotes a methylene group wherein one or two hydrogenatoms independently of one another may be replaced in each case by aC₁₋₃-alkyl group or a hydrogen atom may be replaced by the group—(CH₂)_(p)—R_(f), while p denotes one of the numbers 0, 1, 2 or 3 andR_(f) denotes a hydroxycarbonyl, C₁₋₃-alkoxycarbonyl,N-(C₁₋₃-alkyl)-amino-carbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,N-(C₁₋₃-alkoxy-carbonylmethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl,N-(carboxymethyl)-N-(C₁₋₃-alkyl)-aminocarbonyl or a 4- to 7-memberedcycloalkyleneimino-carbonyl group or (ii) m denotes the number 0, ndenotes the number 0 and A denotes a —CH₂—CH₂— group, or (iii) m denotesthe number 1, n denotes the number 0 and A denotes a —CH₂— group, thegroups R₁ to R₄ are defined as in claim 2, but R₁ in the 4 position isbound to the phenyl group contained in formula I and Ar denotes a phenylgroup disubstituted by the groups R₅ and R₆, while R₅ is bound in the 3position if R₆ denotes a hydrogen atom, or is bound in the 5 position ifR₆ assumes a meaning other than the hydrogen atom, and denotes anamidino group optionally substituted by one or two C₁₋₃-alkyl groups, ahydroxy, C₁₋₆-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl orphenylcarbonyl group, or an amino-C₁₋₃-alkyl orC₁₋₃-alkylamino-C₁₋₃-alkyl group and R₆ denotes a hydrogen atom or ahydroxy, C₁₋₃-alkoxy, carboxy-C₁₋₃-alkoxy, C₁₋₃-alkoxy-carbonyloxy- orC₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy group bound in the 2 position, or asalt thereof.
 4. A compounds of the formula I according to claim 1,wherein: (i) m denotes the number 0, n denotes the number 1 and Adenotes a methylene group wherein a hydrogen atom may be replaced by amethyl, hydroxycarbonyl, C₁₋₃-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl,dimethylaminocarbonyl, pyrrolidin-1-yl-carbonyl,C₁₋₃-alkylaminocarbonylmethyl,N-(hydroxy-carbonyl-methyl)-N-(C₁₋₃-alkyl)-amino-carbonyl-methyl,N-(C₁₋₃-alkoxy-carbonyl-methyl)-N-(C₁₋₃-alkyl)-amino-carbonyl-methyl,hydroxycarbonylmethyl, C₁₋₃-alkoxy-carbonylmethyl ordimethylaminocarbonylmethyl group, R₁ is bound in the 4 position of thephenyl group of formula I and denotes a C₅₋₇-cycloalkylamino group whichmay be substituted at the amino nitrogen atom by a C₁₋₃-alkyl,C₁₋₃-alkylcarbonyl, amino-C₁₋₃-alkylcarbonyl, carboxy-C₁₋₃-alkylcarbonylor C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-carbonyl group, a 4- to 7-memberedcycloalkyleneiminocarbonyl group or a 2,5-dihydropyrrol-1-yl-carbonylgroup, R₂ denotes a hydrogen atom or a C₁₋₃-alkyl, ethenyl, ethynyl,trifluoromethyl or trifluoromethoxy group bound in the 3 position or, ifR₃ denotes a C₁₋₃-alkyl group, in the 5 position of the phenyl group informula I or a chlorine or bromine atom bound in the 3 position, R₃denotes a hydrogen atom or a C₁₋₃-alkyl group bound in the 2 position ofthe phenyl group in formula I, R₄ denotes a hydrogen atom and Ar denotesa phenyl group disubstituted by the groups R₅ and R₆, while R₅ is boundin the 3 position if R₆ denotes a hydrogen atom, or is bound in the 5position if R₆ assumes a meaning other than the hydrogen atom, anddenotes an amidino group optionally substituted by aC₁₋₆-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonylgroup, or a aminomethyl group and R₆ denotes a hydrogen atom or ahydroxy or C₁₋₃-alkoxy-carbonyloxy group bound in the 2 position, or asalt thereof.
 5. A compound of the formula I according to claim 1,wherein: (i) m denotes the number 0, n denotes the number 0 and Adenotes a —CH₂—CH₂— group, or (ii) m denotes the number 1, n denotes thenumber 0 and A denotes a —CH₂— group, R₁ denotes a 4- to 7-memberedcycloalkyleneiminocarbonyl or 2,5-dihydropyrrol-1-yl-carbonyl groupbound in the 4 position of the phenyl group of formula I, R₂ denotes ahydrogen atom or a substituent selected from fluorine, chlorine,bromine, C₁₋₃-alkyl and trifluoromethyl bound in the 3 position or, ifR₃ denotes a C₁₋₃-alkyl group, bound in the 5 position of the phenylgroup in formula I, R₃ denotes a hydrogen atom or a C₁₋₃-alkyl groupbound in the 2 position of the phenyl group in formula I, R₄ denotes ahydrogen atom and Ar denotes a phenyl group disubstituted by the groupsR₅ and R₆, wherein R₅ is bound in the 5 position and denotes an amidinogroup optionally substituted by one or two C₁₋₃-alkyl groups, aC₁₋₆-alkoxy-carbonyl or phenylcarbonyl group and R₆ denotes a hydroxygroup bound in the 2 position, or a salt thereof.
 6. A compound selectedfrom the group consisting of: (1)2-(5-carbamimidoyl-2-hydroxy-phenyl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-ethylamine,(2)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine,(3)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzylamine,(4)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(5)N-(5-carbamimidoyl-2-hydroxy-benzyl)-2,5-dimethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(6)N-(3-carbamimidoyl-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(7)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(8)N-(5-aminomethyl-2-hydroxy-benzyl)-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(9)2-(3-aminomethyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-aceticacid-N-ethylamide, (10)3-(3-aminomethyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid-N-ethylamide, (11)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-ethoxy-carbonyl-propionyl)amino]-benzamide,(12)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-acetyl-N-cyclobutyl-amino)-benzamide,(13)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-(N-cyclopentyl-N-methyl-amino)-benzamide,(14)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-cyclopentyl-N-(3-carboxy-propionyl)-amino]-benzamide,(15)N-(5-carbamimidoyl-2-hydroxy-benzyl)-4-cyclopentylamino-3-methyl-benzamide,(16) ethyl2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-acetate,(17)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid, (18)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(2-aminoacetyl)-N-cyclopentyl-amino]-benzamide,(19)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzamide,(20)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-chloro-4-(pyrrolidin-1-yI-carbonyl)-benzamide,(21) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(22) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(23) ethyl3-(3-carbamimidoyl-phenyl)-3-{3-methyl-4-[N-(3-amino-propionyl)-N-cyclopentyl-amino]-benzoylamino}-propionate, (24) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(25) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionate,(26) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(27) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(28) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionate,(29)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, (30)3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, (31)3-(3-carbamimidoyl-phenyl)-3-[3-chloro-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, (32)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(2,5-dihydropyrrol-1-yl-carbonyl)-benzoylamino]-propionicacid, (33)3-(3-carbamimidoyl-phenyl)-3-[3-ethynyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid, (34)3-(3-carbamimidoyl-phenyl)-3-[3-ethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, (35)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-methyl-N-(hydroxycarbonylmethyl)-amide, (36)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(hydroxycarbonylmethyl)-N-(n-propyl)-amide, (37)3-(3-carbamimidoyl-phenyl)-3-[3-ethenyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid, (38)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid-N,N-dimethylamide, (39)N-[1-(3-carbamimidoyl-phenyl)-2-oxo-2-(pyrrolidin-1-yl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(40)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid-N,N-dimethylamide, (41)2-(3-carbamimidoyl-phenyl)-2-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-aceticacid-N-ethylamide, (42)3-(3-carbamimidoyl-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoyl-amino]-propionicacid-N-ethylamide, (43)3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-3-(3-carbamimidoyl-phenyl)-propionicacid-N-(ethoxycarbonylmethyl)-N-(n-propyl)-amide, (44)N-[-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(45)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-3-bromo-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(46)N-[1-(5-carbamimidoyl-2-hydroxy-phenyl)-ethyl]-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(47) ethyl3-(3-carbamimidoyl-phenyl)-3-[3-trifluoromethyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,(48)N-(5-carbamimidoyl-2-hydroxy-benzyl)-3-trifluoromethoxy-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(49)3-(5-carbamimidoyl-2-hydroxy-phenyl)-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionicacid, (50) ethyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,(51) ethyl3-[3-N-(n-hexyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,(52) n-propyl3-[3-N-(phenylcarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,(53) ethyl3-[3-N-(2,2,2-trichloroethyloxycarbonyl)-amidino-phenyl]-3-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzoylamino]-propionate,(54)N-{5-[N-(n-hexyloxycarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(55)N-{5-[N-(phenylcarbonyl)-amidino]-2-hydroxy-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,(56)N-[5-(N-hydroxy-amidino)-2-hydroxy-benzyl]-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamideand (57)N-{5-[N-(phenylcarbonyl)-amidino]-2-(ethyloxycarbonyloxy)-benzyl}-3-methyl-4-(pyrrolidin-1-yl-carbonyl)-benzamide,or a derivative thereof wherein at least one amidino group present issubstituted by a C₁₋₆-alkoxycarbonyl or phenylcarbonyl group, or a saltthereof.
 7. A physiologically acceptable salt of a compound according toclaim 1, 2, 3, 4, 5 or 6, with the exception of those compounds whereinAr denotes a phenyl or naphthyl group substituted by the groups R₅, R₆and R₇, and R₅ denotes a cyano group.
 8. A pharmaceutical composition acompound according to claim 1, 2, 3, 4, 5 or 6, with the exception ofthose compounds wherein Ar denotes a phenyl or naphthyl groupsubstituted by the groups R₅, R₆ and R₇, and R₅ denotes a cyano group,or a physiologically acceptable salt thereof, together with one or moreinert carriers and/or diluents.
 9. A method for treating thrombusformation which method comprises administering to a host in need of suchtreatment an antithrombotic amount of a compound according to claim 1,2, 3, 4, 5 or 6, with the exception of those compounds wherein Ardenotes a phenyl or naphthyl group substituted by the groups R₅, R₆ andR₇, and R₅ denotes a cyano group, or a physiologically acceptable saltthereof.